Lung Adenocarcinoma Cancer Research Articles

Abstract 526: RMC-9805, a first-in-class, mutant-selective, covalent and oral KRASG12D(ON) inhibitor that induces apoptosis and drives tumor regression in preclinical models of KRASG12D cancers

Abstract KRASG12D is the most frequent KRAS mutation in human cancers, with the highest prevalence in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). RMC-9805 is a first-in-class, oral, mutant-selective covalent inhibitor of the GTP-bound and active RAS(ON) form of KRASG12D. The formation of a stable, high affinity tri-complex between RMC-9805, KRASG12D and cyclophilin A results in the suppression of signaling downstream of KRASG12D(ON) by disrupting its interactions with downstream effectors such as RAF kinases. RMC-9805 treatment caused selective and persistent modification of KRASG12D leading to deep and durable suppression of RAS pathway activity, inhibition of cell proliferation, and apoptosis induction in KRASG12D human cancer cell lines in vitro and tumor models in vivo. In a mouse clinical trial with KRASG12D xenograft tumor models, RMC-9805 administered orally as a single agent was well tolerated and induced objective responses in 7 of 9 PDAC PDX and CDX models and 6 of 9 NSCLC PDX models, as assessed by mRECIST. In the few models that exhibited sub-optimal responses to RMC-9805 monotherapy, combination treatment with various RAS Companion Inhibitors improved depth and/or duration of anti-tumor response. In contrast to RASMUTANT NSCLC and PDAC, CRC tumors are less dependent on RAS driver mutations. For example, a more heterogeneous response to KRASG12C inhibitors has been reported in CRC than in NSCLC patients, suggesting combinations will be desired to achieve significant clinical benefit in CRC. Likewise, RMC-9805 monotherapy is less active in CRC models at doses that were highly active in KRASG12D NSCLC and PDAC models. However, combinations of RMC-9805 with vertical or parallel pathway RAS Companion Inhibitors such as SHP2, mTORC1 or RASMULTI(ON) inhibitors, achieved objective response rates up to 60% and delayed the onset of resistance in tumor models in vivo. RMC-9805 also synergized with anti-PD1 therapy in KRASG12D tumors in immune-competent animal models by shaping a favorable tumor immune microenvironment through cytokine modulation. In addition, RMC-9805 engaged the adaptive immune system by increasing presentation and recognition of tumor antigens, promoting a diversification of the TCR repertoire, and inducing immunological memory. Overall, RMC-9805 monotherapy elicited tumor regressions in most preclinical PDAC and NSCLC cancer models harboring KRASG12D. Furthermore, RMC-9805 combination therapies drove regressions in CRC models relatively less responsive to monotherapy. Supported by these findings, RMC-9805 is currently in IND-enabling development to permit clinical evaluation of single agent and combination strategies in patients with KRASG12D tumors. Citation Format: Lingyan Jiang, Marie Menard, Caroline Weller, Zhican Wang, Les Burnett, Ida Aronchik, Shelby Steele, Mike Flagella, Ruiping Zhao, James W W. Evans, Shook Chin, Kang-Jye Chou, Yunming Mu, Michael Longhi, Laura McDowell, John E. Knox, Adrian Gill, Jacqueline A. Smith, Mallika Singh, Elsa Quintana, Jingjing Jiang. RMC-9805, a first-in-class, mutant-selective, covalent and oral KRASG12D(ON) inhibitor that induces apoptosis and drives tumor regression in preclinical models of KRASG12D cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 526.

Abstract 5477: An investigation to study differential gene expression of lung cancer cells, tumor associated macrophages, and bone marrow derived mesenchymal stems cells in the tumor microenvironment

Abstract Cancer is a public health crisis affecting approximately 19.3 million globally, annually. Lung cancer has the highest percentage of incidence and is responsible for 27% of cancer-related deaths. The prevalence of lung cancer worldwide led us to investigate differential gene expression in lung adenocarcinoma and small cell lung cancer cell lines in comparison to a healthy lung cell line. We also investigated the effect of lung tumor microenvironment to bone marrow derived pluripotent mesenchymal stem cells (PMSC) and tumor associated macrophages. This research involved cancer and healthy cell line culture with appropriate medium. Whole transcriptomic and small non-coding RNA sequencing and analysis by Ingenuity Pathway Analysis (Qiagen, USA), Quantitative RT-PCR and ELISA assays. We further studied morphological changes and differential gene expression in extracellular vesicles(exosomes) isolated from the TAM and TME exposed PMCs by atomic force microscopy and RNA sequencing techniques. The results of our investigation showed differential gene expression and novel core canonical pathways in the lung cancer cells, TME exposed TAM, and PMSC. We also observed morphological changes in TME derived exosomes from TAM and PMSC. RNA sequencing results showed differential gene expression of both coding and non-coding RNAs including tRNA fragments. Thus, our findings of this investigation led to identification of multiple cancer related genes and small non-coding microRNA, long non-coding RNA, and tRNA fragments which will have potential diagnostic and therapeutic target value that demands further future research. Acknowledgement: This research is supported by a grant from US NIH-NIGMS- 5T34GM100831-08 and US-NIH Grant# U 54 MD007597-31-5959. Citation Format: Hirendra N. Banerjee, Joseph Hedley, Cheslsey Aurelus, Narendra Banerjee, Kuldeep Rawat, Quentin Reaves, Shennel Brown, Darla Gilmartin, Makieyah Liverman, Jazmine Cuffee, Elizabeth Cagle, Erik Armstrong, Brent Lake, Santosh Mandal, Somiranjan Ghosh, Stephen Beebe, Kamal Asadipour, Christopher Krauss, Santanu Bhattacharya, Tanmay Kulkarni, Zahidur Abedin. An investigation to study differential gene expression of lung cancer cells, tumor associated macrophages, and bone marrow derived mesenchymal stems cells in the tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5477.

Abstract 515: Discovery of potent and orally available small molecule inhibitors of the SOS1-KRAS interaction

Abstract Abnormal activating mutation of KRAS is frequently found in many human cancers, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). KRAS activating mutations lead to hyperactivation of the MAPK/ERK signaling pathway, resulting in promotion of cell proliferation and growth. SOS1 is one of the major guanine nucleotide exchange factors (GEFs) that regulates RAS proteins including KRAS. Since SOS1 plays a critical role in converting the GDP-bound inactive KRAS “off” state to the GTP-bound active KRAS “on” state, disruption of SOS1 and KRAS protein-protein interaction would be effective to block KRAS-driven oncogenic signaling regardless of its mutation status. Importantly, SOS1 activity is crucial during the reactivation of the KRAS/MAPK signaling upon the treatment of RAS/MEK/ERK inhibitors, thus a SOS1 inhibitor would be an effective therapeutic option to treat KRAS-driven tumors in combination with RAS pathway inhibitors. We developed potent, selective, and orally available small molecules that effectively disrupt the interaction between SOS1 and KRAS. Current lead compounds originated from a virtual screening displayed excellent ADME and PK profiles. In cellular assays, a robust reduction of phospho-ERK level and cancer cell growth were shown. We also observed excellent in vivo antitumor activity in the mouse xenograft models. Moreover, combination with Sotorasib synergistically inhibited tumor cell growth both in vitro and in vivo. Overall, our SOS1 inhibitors demonstrate great therapeutic potential for cancer patients with KRAS mutations. Citation Format: Ha Na Yu, Dong Hyuk Ki, Joonwoo Nam, Eun-Jung Kim, Sungeun Kim, Hunmi Choi, Jieun Kim, Jihyun Yu, Donggeon Kim, Dohyun Park, Kyeong Jin Yoon, Seongin Jo, So-Hyeon Hwang, Sang Kyun Lim, Young Sook Shin, Wooseok Han. Discovery of potent and orally available small molecule inhibitors of the SOS1-KRAS interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 515.

Abstract 881: Desmocollin-3 and tumor immune microenvironment: Bioinformatics evaluation

Abstract Desmocollin-3 (DSC3) is a desmosomal adhesion molecule responsible for integrity and cell adhesion under normal physiological condition. Its expression is altered during carcinogenesis. DSC3 is a p53 responsive gene. Like other adhesion molecules, it is described to provide barrier for immune infiltration of tumor. To identify a specific immune gene signature related to DSC3, spearman correlation coefficient was determined for 207 immune related genes using Cbioportal in cancer having high and low level of DSC3 gene expression .We classified renal adenocarcinoma lung, hepatocellular carcinoma and renal cancer as DSC3low and squamous lung cancer, cervical cancer and head and Neck cancer as DSC3high based on DSC3 gene expression level. In DSC3high group, six genes were found to be correlated (Spearman correlation ≥ 0.3) with DSC3 expression (Table), while none of the 207 immune related genes were correlated with DSC3low expression. Of genes with positive correlation, CD44 is a marker for stem cell and is associated with resistance to chemotherapy while S100A12 and TOLLIP are associated with carcinogenesis and inflammation. Of immune genes with negative correlation, GATA6 is a tumor suppressive gene, IL-12A is responsible for T-cell-independent induction of IFNγ and CD63 is associated with survival as described in lung cancer. This findings suggests DSC3high expression may be associated with poor prognosis compared DSC3low . DSC3 expression is specific for squamous lung cancer and is used to differentiate it from adenocarcinoma lung. Squamous lung cancer is also known to have poor prognosis compared to adenocarcinoma of lung. We will be presenting full details about 207 selected genes and their correlation with DSC3 in our presentation. Table: Spearman’s correlation of DSC3 with Immune genes DSC3 expression Immune genes with positive spearman’s correlation Immune genes with negative spearman’s correlation Cancer Median RSEM (N) CD44 S100A12 TOLLIP CD63 GATA6 IL12A LUSC 6208 (n=501) 0.4 0.3 0.4 -0.4 -0.3 -0.3 CESC 10086 (n=306) 0.6 0.6 0.6 -0.6 -0.4 -0.4 HNSC 15287(n=522) 0.3 0.3 0.3 -0.5 -0.3 -0.4 KIPAN 1.5 (n=720) < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 LIHC 2.0 (n=231) < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 LUAD 10 (n=496) < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 < 0.3 Citation Format: Arpit Dheeraj, Bakulesh M. Khamar, Chandreshwar P. Shukla, Nayan K. Jain, Rajiv I. Modi. Desmocollin-3 and tumor immune microenvironment: Bioinformatics evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 881.

Abstract 3723: Identification and functional characterization of long noncoding RNAs that regulate TGF-<&946;>-Smad pathway as Smad co-factors

Abstract TGF-β-Smad pathway participates in various biological processes such as development, differentiation, growth regulation, and cancer progression including epithelial-mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) also involved in carcinogenesis and cancer malignancies. To identify lncRNAs regulating TGF-β-Smad pathway, we comprehensively identified lncRNAs induced by TGF-β and found and reported a lncRNA ELIT-1 (EMT-associated lncRNA induced by TGF-β-1) which was induced by TGF-β and promoted EMT by facilitating TGF-β-Smad signaling. ELIT-1 bound to Smad and participated in expression of TGF-β target genes including Snail. Prognosis of lung adenocarcinoma and gastric cancer patients with high expression of ELIT-1 was poor suggesting that ELIT-1 may be useful as a novel prognostic and therapeutic target. Recently, we found that lincNMR (long intergenic noncoding RNA-nucleotide metabolism regulation) was induced via TGF-β-Smad pathway in various cell lines. Moreover, RNA-seq analysis using lincNMRs-depleted cells indicated that lincNMRs was involved in expression of APOBEC3B, a cytidine deaminase, promoting C to U mutation and highly expressed in various human cancers. Although, regulatory mechanisms of APOBEC3B expression have not been fully elucidated, we proved that lincNMRs bound to Smad and promoted the activity of APOBEC3B promoter. These data suggest that lincNMRs participate in APOBEC3B expression by collaborating with TGF-β-Smad pathway. Additionally, high expression of lincNMRs was positively correlated with high expression of APOBEC3B in various cancer cell lines. The high expression of APOBEC3B as well as lincNMR was significantly associated with their poor prognosis in liver and lung cancer patients, suggesting that lincNMR may contribute to tumor malignancy by enhanced expression of APOBEC3B via TGF-β-Smad pathway. Citation Format: Masatoshi Kitagawa, Kosuke Ota, Tatsuya Ohhata, Satoshi Sakai. Identification and functional characterization of long noncoding RNAs that regulate TGF-<&946;>-Smad pathway as Smad co-factors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3723.

Abstract 1644: Dual inhibition of MAT2A and PRMT5 delivers synergistic anti-tumor responses in preclinical models of MTAP-deleted cancer

Abstract Approximately 15% of all tumors harbor deletions in the 9p21 locus that encompass CDKN2A and MTAP. MTAP fuels the adenine and methionine salvage pathways by converting MTA into precursors of building blocks for protein and DNA production. In MTAP-deleted (MTAPdel) tumors, cellular MTA accumulates and partially inhibits the essential protein methyl transferase, PRMT5, through direct displacement of the cofactor S-adenosyl methionine (SAM) from the PRMT5 active site. This context provides therapeutic opportunities, currently under clinical evaluation, to selectively extinguish PRMT5 activity in tumor cells with MAT2A inhibitors that limit SAM synthesis or with direct PRMT5 inhibitors that are MTA-cooperative. Preclinical modeling of these synthetic lethal relationships, and elucidation of their cellular mechanisms of action, suggests efficacy can vary depending upon the extent of MTA accumulation and/or adaptive compensation to PRMT5 inhibition. To potentially maximize therapeutic activity among mechanistically heterogenous MTAPdel tumors, we evaluated combinatorial pathway suppression with MAT2A and PRMT5 inhibitors in MTAPWT and MTAPdel tumor models in vitro and in vivo. We noted synergistic antiproliferative effects when the potent and selective MAT2A inhibitor IDE397 was combined with any of multiple MTA-cooperative PRMT5 inhibitors in MTAPdel cell lines that exhibit sensitivity to each single agent. In vivo, the combination of IDE397 and MTA-cooperative PRMT5 inhibitors were well tolerated, and induced durable tumor regressions, including complete responses, at dose levels well below the maximally efficacious preclinical dose of each individual agent in MTAPdel lung adenocarcinoma and pancreas cancer models H838 and BXPC3. Pharmacodynamic target engagement in the tumor was evaluated by quantitative assessment of symmetric dimethyl arginine (SDMA), as detected by IHC, and indicated earlier onset and greater extent of PRMT5 inhibition by combination treatment as compared to either agent alone. The potentiation of the antitumor response with the combination did not occur in the MTAPWT setting. Thus, combined inhibition of MAT2A and PRMT5 potentially offers a compelling dual synthetic lethal opportunity to address unmet need for the many patients afflicted with MTAPdel cancers. Citation Format: Marcus M. Fischer, Kimberline Gerrick, Brian Belmontes, Katherine Slemmons, Yevgeniy Freyman, Jay Jain, Steve Federowicz, Isaac Bishof, Arjun A. Rao, Melissa Fleury, Zineb Mounir, Mark R. Lackner, Paul E. Hughes, Mike White, Claire L. Neilan. Dual inhibition of MAT2A and PRMT5 delivers synergistic anti-tumor responses in preclinical models of MTAP-deleted cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1644.

Abstract 1563: Concomitant inhibition of Aurora kinase A and WEE1 kinases results in synergistic tumor control and heightens DNA replication stress in head and neck and lung carcinomas

Abstract Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) and lung cancer mainly harbor disruptive mutations in TP53 and/or CDKN2A tumor suppressor genes, which are associated with refractoriness to treatment as well as poor prognosis and survival. Mutational loss of TP53 function fosters elevated expression of Aurora kinase A (AURKA) that plays a crucial role in mitotic progression at G2/M and stabilizes DNA replication forks at S phase. We have previously demonstrated that combined inhibition of AURKA and WEE1, a G2/M checkpoint kinase induced by replication stress, results in synergistic anti-tumor effects in HNSCC in vitro and in vivo. We have now further confirmed synergy using the highly selective AURKA inhibitor VIC1911 in HNSCC and lung cancers harboring TP53 mutations and explored mechanisms of cell death. VIC1911 and adavosertib combination synergistically suppressed cell growth and survival in both 2D- and 3D-culture systems relative to vehicle or single-agent treatment in TP53-mutated HNSCC FaDu and CAL27, and lung cancer A549 and NCI-H358 cells, with no observable toxicity in normal cells, predicting a favorable therapeutic index. Furthermore, combination treatment accelerated mitotic entry and resulted in accumulation of mitotic catastrophe, as demonstrated by time-lapse imaging, and apoptotic cell death as evidenced by cleaved PARP assays. Notably, we found that combination VIC1911 and adavosertib in HNSCC cells drastically slowed and stalled progression of replication forks in DNA fiber analysis (Mean: DMSO=3.117; adavosertib=1.495; VIC1911=0.9757; combination=0.5548 kb/min; P <0.0001) and amplified DNA damage as measured by γH2AX, indicating induction of severe replication stress. In vivo, this combination resulted in significant tumor regression in both HNSCC and lung adenocarcinoma patient-derived and cancer cell-derived xenografted mice compared with either vehicle or single-agent treatment. Taken together, these results suggest that AURKA inhibition increases dependency on WEE1 by enhancing replication stress and mitotic catastrophe, and support clinical evaluation of combined AURKA and WEE1 inhibition as a novel and effective treatment for HNSCC and lung cancer patients with elevated AURKA expression. Citation Format: Jong Woo Lee, Sundong Kim, Sebastian Cruz-Gomez, Jackie Shi, Cindy Yang, Barbara Burtness. Concomitant inhibition of Aurora kinase A and WEE1 kinases results in synergistic tumor control and heightens DNA replication stress in head and neck and lung carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1563.

Abstract 3516: Metastatic colonization requires a proliferative pause linked to vascular co-option

Abstract The physical interaction between metastasis-initiating cells and the pre-existing capillary network (a process known as vascular co-option) is critical during the initial stages of multi-organ metastasis in cancer. As such, this process might provide an opportunity to prevent metastasis. As part of the process of vascular co-option, we observed that brain metastatic cells in the perivascular niche temporarily enter into a novel cell state characterized by a decreased proliferation before resuming their aggressive growth to colonize the organ. Transcriptomic analysis of co-opting metastatic cells confirmed downregulation of MYC signatures, mitotic cell cycle and increased stemness properties. By focusing on one of the top upregulated transcription factors in co-opting cells: MXD4, a MYC antagonist; we have been able to dissect the relevance of this cellular state, that we termed proliferative pause, both respect to the maintenance of the interaction with the vasculature and to the ability to generate macrometastases. As such, targeting MXD4 in lung adenocarcinoma and triple-negative breast cancer metastatic models reduced multi-organ metastases to a level that translates into increased overall survival. Mechanistically, this obliged proliferative pause is linked to a cellular response to the increasing environmental pressure involved in organ colonization. For instance, we found that crossing the blood-brain barrier induced an increased DNA damage due to mechanical constrains leading to nuclear deformation. However, the MXD4-dependent proliferative pause during vascular co-option allows metastatic cells to repair this damage to continue the colonization process. Given the enormous potential to prevent metastasis and our findings dissecting the proliferative pause status, we developed a therapeutic strategy to target vascular co-opting cells. As part of the molecular profile of co-opting cells, we validated their high dependency on Bcl proteins. As such, we have used a Bcl-2 inhibitor (obatoclax) permeable to the blood-brain barrier to target these cells in preventive scenarios. Beyond the preventive therapeutic assays in vivo, we have applied additional clinically-relevant models where preventive strategies could easily translate into the clinical practice. As such, obatoclax post-surgery provided a survival benefit by preventing relapse, as the cells left behind after the local therapy are vascular co-opting cells. Furthermore, our national network of brain metastasis (RENACER) provided us with fresh neurosurgeries and, in a limited cohort of 10 surgeries with extended resections, we were able to identify invasive fronts with metastatic cells co-opting the vasculature. The use of obatoclax to target these cancer cells, which are the seeds of relapse post-surgery, confirmed that targeting vascular co-option could be a novel strategy to prevent metastasis in a clinically relevant situation. Citation Format: Pedro García-Gómez, Diana Retana, Pablo Sanz-Martínez, Irene Salgado-Crespo, Carolina Hernández-Oliver, Maria Isabel García, Oliva Sánchez, Kevin Troulé-Lozano, Verona Villar-Cerviño, Miguel Lafarga-Coscojuela, Fátima Al-Shahrour, RENACER Red Nacional de Metástasis Cerebral, Manuel Valiente. Metastatic colonization requires a proliferative pause linked to vascular co-option [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3516.

Abstract 1841: TAK-500 is a clinical stage immune-cell directed antibody drug conjugate (iADC) inducing STING activation in CCR2-expressing intratumor myeloid cells and favorable immunomodulation

Abstract Introduction: Myeloid cells are present in the tumor microenvironment (TME) of most human solid cancers, playing an essential role to influence local immunomodulatory functions. STING signaling in intratumor myeloid cells can enhance interferon (IFN) production leading to enhanced local innate and adaptive immunity, and synergism with other anti-tumor mechanisms. Here, we used a novel iADC, TAK-500, to selectively activate STING in CCR2-expressing cells. This approach enables systemic delivery and favors intratumor accumulation of a STING agonist to potentially achieve anti-tumor activity. Methods: TAK-500 and mTAK-500, a murine surrogate, were employed to study the immunomodulatory role and anti-tumor effects in preclinical models. CCR2 protein expression was characterized in the TME of >1,000 primary human tumors including non-small cell lung cancer (NSCLC, 2 cohorts, N= 411), colorectal carcinomas (CRC, 2 cohorts, N=350) and pancreatic ductal adenocarcinomas (PDAC, 1 cohort, N=228) represented in tissue microarrays using multiplexed quantitative immunofluorescence (mQIF). Results: TAK-500 triggered dose-dependent monocyte activation in vitro. mTAK-500 induced robust activation of innate and adaptive immune responses both in vitro and in vivo. In syngeneic mouse models with CCR2 expressing intratumoral myeloid cells, mTAK-500 treatment caused accumulation and activation of CD8+ effector T-cells in the TME resulting in prominent anti-tumor activity and enhanced survival. The baseline levels of CCR2-expressing mMDSCs in mouse models positively associated with anti-tumor response to mTAK-500. mQIF analysis of human tumors confirmed high expression of CCR2 in myeloid cells, lower expression in tumor infiltrating lymphocytes (TILs) and absence in tumor epithelial cells. Using an mQIF panel for simultaneous measurement of DAPI, CK, CCR2, CD11b and CD68, we identified CCR2 protein expression in 94% of NSCLCs, 87% CRCs and 89% PDACs. The levels of CCR2 protein were significantly higher in NSCLC than in CRC and PDAC. In NSCLC, high CCR2 protein in myeloid cells was associated with the presence of activating EGFR/KRAS mutations and increased CD8+ TILs and local PD-L1 expression. In CRC, higher levels of CCR2 in CD68+ macrophages were seen in tumors harboring microsatellite instability than in microsatellite stable carcinomas. Conclusion: The iADC TAK-500 and mTAK-500 induces CCR2-dependent immune cell activation and anti-tumor effect. CCR2 is highly expressed in intratumor myeloid cells from NSCLC. High CCR2 is associated with enhanced local adaptive immune responses and specific clinical/molecular tumor subsets. TAK-500 is currently being evaluated clinically as a single agent and in combination with pembrolizumab in adults with select locally advanced or metastatic solid tumors (NCT05070247). Citation Format: Kurt A. Schalper, Atsushi Matsuda, Michelle Ganno-Sherwood, Angel E. Maldonado-Lopez, Emily Rosentrater, Angelo Porciuncula, Dong Mei Zhang, Camilla L. Christensen, Samantha A. Merrigan, Tiquella Hatten, Hong Myung Lee, Min Young Lee, Linlin Dong, Jian Huang, Natasha Iartchouk, Jianing Wang, He Xu, Tomoki Yoneyama, Konstantin I. Piatkov, Carole E. Harbison, Alex Parent, Neil Lineberry, Adnan O. Abu-Yousif, Vicky Appleman. TAK-500 is a clinical stage immune-cell directed antibody drug conjugate (iADC) inducing STING activation in CCR2-expressing intratumor myeloid cells and favorable immunomodulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1841.

Abstract 5370: New oncology target identification and validation platform combining artificial intelligence and preclinical pharmacology

Abstract Despite major advances in cancer therapy in the last decades, treatment resistance can develop over time. Precision medicine allows for the successful implementation of targeted therapies and stratification of patients, but treatment resistance remains a major obstacle in patient management. The identification and validation of new targets associated with cancer resistance remains a major challenge. The great diversity of molecular mechanisms involved in treatment resistance phenomena, whether intrinsic (de novo or primary) or acquired (secondary), constitutes a real therapeutic challenge for patient care. A better understanding of resistance mechanisms would allow to explore new therapeutic strategies to circumvent these phenomena in different types of cancer. The OncoSNIPE® project was developed in this context as part of a multicenter and collaborative clinical study (NCT04548960) in more than 800 chemo-naive adult patients. The objective of this project was to identify early and/or late markers of treatment resistance in three different pathologies for which resistance problems are encountered: triple negative breast cancer (TNBC) or luminal B, locally advanced or metastatic non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC). The program included traditional clinical and whole exome sequencing (WES) monitoring of patient biopsies (Exom-seq and RNA-seq) at diagnosis and relapse, monitoring of blood markers (RNA-seq and Proteomics – Cytokine) at diagnosis, and the evaluation of best therapeutic responses and relapse. The program used bioinformatics, artificial intelligence, statistical learning and semantic enrichment approaches to discover the diversity of mechanisms involved in these resistances and to identify new therapeutic targets, through hetero-modal data including clinical, genomic, transcriptomic, immunological and radiomic dimensions. Subsequently, a specific flowchart for target validation was applied to the resulting list, considering the target's developmental potential, its essentiality, prior knowledge (database mining) and home-made score of the link between the target and the disease. Finally, new targets were prioritized using weighting parameter and heuristic approximation based on the Crank algorithm. Experimental work on multiple targets began in the laboratory, initially in vitro, using 2D and 3D cell culture (including cells from patient-derived xenografts) and molecular interference. A wide variety of intrinsic or acquired molecular mechanisms involved in treatment resistance are being evaluated as candidates for diagnostic and therapeutic development. Citation Format: Sebastien Vachenc, Nicolas Ancellin, Didier Grillot, Kenji Shoji, Joanna Giemza, Nathalie Jeanray, Leila Outemzabet, Salvatore Raieli, Lamine Toure, Olivier Duchamp, Fabrice Viviani, Philippe Genne, Jan Hoflack, Stéphane Gerart. New oncology target identification and validation platform combining artificial intelligence and preclinical pharmacology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5370.

Abstract 2472: Interdisciplinary method to elucidate the interaction between brain microenvironment and cancer cells

Abstract Cancer cells may escape from host immunity to form distant metastases. We have made an original imaging model of brain metastasis (IBrM) to show a heterogeneous interaction between microglia, the tissue macrophages in the brain, and cancer cells in the brain niche. Here we report that enhanced microglial elimination of cancer cells is a new potential treatment for metastatic brain tumors by inhibiting their engraftment. First, to explore factors that favor survival of cancer cells in the brain microenvironment, mouse lung cancer cells (CMT167) were injected through the internal carotid artery, and after 4, 7, 10, and 13 days, surviving cancer cells in the mouse brain were collected and RNAseq was performed. In particular, we focused on CD24/CD7/PD-L1, a known factor that escapes phagocytosis by macrophages. The expression of CD24/CD47 in cancer cells gradually increased, while that of PD-L1 decreased. Next, we injected adenocarcinoma lung cancer cells (LUCs, CMT167) or breast cancer cells (BCCs, E0711) expressing mCherry via the internal carotid artery of the CX3CR1-EGFP mice, whose microglia had been specifically labeled with EGFP. The microglia and LUCs/BCCs were visualized in vivo simultaneously by two-photon microscopy for 14 days. The tumor fate and microglial response against cancer cells were evaluated at single cell resolution in the IBrM. Microglial phagocytosis was significantly increased by single deletion of CD47 or CD24 compared with WT cells. Combined deletion of CD47 and CD24 also synergically increased microglial phagocytosis, resulting in reduced IBrM and prolonged mouse survival. By contrast, deletion of PD-L1 did not enhance microglial phagocytosis or prolong survival. The pharmacological (PLX3397) or genetic conditional (Siglechdtr het/CX3CR1GFP het) conditional depletion of microglia canceled both the increased phagocytosis and the extended survival time, suggesting that the effect of “don't eat me” signals was microglia dependent. The extended survival time was also observed in IBrM using BALB-c nu/nu, that suggest the effect is not dependent on matured T-lymphocytes.These results indicate that novel function of microglia against cancer cells, and suppression of both CD24 and CD47 in cancer cells and enhances microglial phagocytic activity and suppresses the metastatic formation. We are further developing a method for isolating LUCs fluorescently labeled in vivo using holographic 2-photon microscopy for evaluating single cell gene expression profiles. Using the novel techniques, the spatio-temporal information can be integrated across the molecular, cellular and tissue levels that allow us to further investigate the dynamic behavior of not only tumors, but also microglia and neurons. Citation Format: Takahiro Tsuji, Hiroaki Wake, Mariko Shindo, Rahadian Y. Hartantio, Misuzu Horikoshi, Daisuke Kato, Hiroaki Ozasa, Toyohiro Hirai. Interdisciplinary method to elucidate the interaction between brain microenvironment and cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2472.

Abstract 3583: Novel MRI contrast system using halloysite nanotubes embedded with iron-platinum nanoparticles for the regulation of the CHST11 expression for cancer treatment

Abstract Topic: TB Tumor Biology (TB03) In Vivo Imaging. Multifunctional nanocomposites have been a popular research target in recent years. This research aims to produce magnetic nanocomposites with high saturation magnetization (Ms) and good biocompatibility to improve the disadvantage of iron-oxide was easy decomposition in the biological environment and overcome the unclear contrast problem of T2-weighted magnetic resonance imaging (MRI) of lung adenocarcinoma. In order to fit the suitable size of iron-based nanoparticles embedded into the halloysite nanotubes (HNT), the iron-platinum (FePt) nanoparticles were chosen as the MRI’s core materials. The FePt@HNT nanocomposites have low toxicity, and superparamagnetism is expected to be used in biomedical therapy and magnetic separation for disease treatment and environmental protection. Lung adenocarcinoma cancer cells grow in situ, usually invade, and are frequently recurrent after treatment. Since CHST11-mediated gene regulation may serve as a possible means of reducing tyrosine kinase inhibitor (TKI)-induced mitotic cell death, CHST11 modulation of integrin signaling may help lung cancer cells enhance their resistance to gefitinib. To enable the FePt@HNT nanocomposite to be effective in treating lung tumors, we designed miRNAs that inhibit CHST11 expression in an attempt to diagnose lung adenocarcinoma concurrently for treatment. Keywords: Magnetic resonance imaging, halloysite nanotubes, FePt nanoparticles, CHST11, Lung adenocarcinoma

Abstract 1013: Circulating H3K27 methylated nucleosome concentration in lung cancer improves the contributive value of ctDNA molecular profiling result at diagnosis

Abstract Background: In patients with advanced lung adenocarcinoma cancers, a subset can be cured by radiotherapy, and/or combined regimens, including chemotherapy, immunotherapy, or targeted therapies based on somatic molecular profiling. Nucleosomes are basic elements of chromatin, composed of 147bp DNA wrapped around an octamer of histones. Cell-free DNA (cfDNA) and nucleosomes are released into the bloodstream upon cell death. In addition to genetic somatic alterations, epigenetic modifications are found to play a key role in tumorigenesis of different cancers. The trimethylated histone H3 at lysine 27 (H3K27Me3) is well known as a transcription-repressive mark and proven to be involved in tumorigenesis, cell cycle progression and proliferation dysregulation. However, the concentration of circulating nucleosomes, as a biomarker of the contributive value of circulating tumor DNA (ctDNA) molecular profiling in patient management at diagnosis has not previously been investigated. Patients and Methods: Plasmas were retrospectively collected from patients with NSCLC at initial diagnosis before treatment (CIRCAN’s cohort, N= 198) and from healthy donors (N=100). We carried out targeted next-generation sequencing (NGS) on paired plasmas. Samples were divided in two sub-groups based on the genetic results: ctDNA negative or positive for presence of somatic alterations. The concentration of global circulating nucleosomes as well as specific methylated marks: H3K4Me2-, H3K9Me3-, H3K27Me3- or H3K36Me3-nucleosomes were measured using chemiluminescent Nu.Q® immunoassays (Belgian Volition SRL, Belgium). Results: Among all the different nucleosome forms evaluated, the highest coefficient correlations with cfDNA concentration were observed for H3K27Me3-nucleosomes (r=0.72, p<0.0001). At a cut-off of 14 ng/ml of H3K27Me3-nucleosomes Nu.Q® assay showed a sensitivity of 69.2% (n=137) at 95% specificity for lung cancers vs healthy donors (AUC= 0.92). Interestingly, by combining H3K37Me3 level and ctDNA molecular profile, we found a contributive diagnostic value of molecular profiling results in 77% of the plasmas versus only 40% using NGS alone as per current practice. 32% of plasmas were positive for both H3K27Me3 and ctDNA; 37% are H3K27Me3-positive but ctDNA-negative; 8% of the samples were ctDNA-positive/H3K27Me3-negative and 23% are negative for both H3K27Me3 and ctDNA. Conclusions: High levels of Nu.Q® H3K27Me3 and the absence of detecting somatic alterations strongly support the presence of non-mutated ctDNA in the corresponding plasma. This greatly improves the confidence in the negative molecular results in cfDNA in LC. This may allow the indication of individualized therapeutic regimens with a short-time medical decision and may reduce invasive tissue re-biopsies. Citation Format: Arnaud Gauthier, Julie Candiracci, Emmanuel Grolleau, Gaelle Lescuyer, David Barthelemy, Christine Haon, Florence Geiduer, Margaux Raffin, Nathalie Hardat, Julie Balandier, Rémi Rabeuf, Anne-Sophie Wozny, Claire Rodriguez-Lafrasse, Guillaume Rommelaere, Fabien Subtil, Sébastien Couraud, Marielle Herzog, Lea Payen-Gay. Circulating H3K27 methylated nucleosome concentration in lung cancer improves the contributive value of ctDNA molecular profiling result at diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1013.

75TiP A multicenter, open-label, phase II trial evaluating the safety and efficacy of folate receptor alpha (FRα) antibody-drug conjugate (ADC) farletuzumab ecteribulin (FZEC*) in patients with previously treated, metastatic non-small cell lung cancer (NSCLC) adenocarcinoma (AC)

75TiP A multicenter, open-label, phase II trial evaluating the safety and efficacy of folate receptor alpha (FRα) antibody-drug conjugate (ADC) farletuzumab ecteribulin (FZEC*) in patients with previously treated, metastatic non-small cell lung cancer (NSCLC) adenocarcinoma (AC)

Predictive factors associated with pemetrexed acute toxicity

Pemetrexed has shown efficacy as monotherapy or in combination with platinum salts in the treatment of non-small cell lung cancer and mesothelioma. However, severe hematological toxicities induced by pemetrexed-based chemotherapy have been observed. Some studies have suggested that drug interactions may be associated with pemetrexed toxicity. The objective of this study was to determine predictive factors, including drug interactions, associated with pemetrexed toxicity. This retrospective open monocentric study included patients consecutively treated with pemetrexed after a multidisciplinary risk assessment. Patients who experienced toxicity of grade 3 or 4 according to the Common Terminology Criteria for Adverse Events v5.0, or a grade 2 leading to a change in management, during the first four courses of pemetrexed, were assigned to the early limiting toxicities (ELT) group. Univariate and multivariable logistic regression models were used to test the association variables with the occurrence of ELT. Seventy-four patients were included in this study (median age: 67years, with non-small cell lung cancer adenocarcinoma (88%), mesothelioma (7%), or others (5%). Thirty-six patients (49%) were assigned to the ELT group (27 grades 3 and 4; 9 grade 2 with management modification). Three baseline factors were associated with pemetrexed ELT in univariate and multivariate analysis: cystatin clearance (p = 0.0135), albumin level (p = 0.0333), and proton pump inhibitors use (p = 0.035). To conclude, ELT induced by pemetrexed-based treatments occur frequently in cancer patients in a real-world setting. A pretherapeutic assessment before pemetrexed initiation should include three major checkpoints: use of proton pump inhibitors, sarcopenia, and denutrition evaluation.

ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: a multi-omics analysis

BackgroundMetastases are the major cause of cancer-related morbidity and mortality. By the time cancer cells detach from their primary site to eventually spread to distant sites, they need to acquire the ability to survive in non-adherent conditions and to proliferate within a new microenvironment in spite of stressing conditions that may severely constrain the metastatic process. In this study, we gained insight into the molecular mechanisms allowing cancer cells to survive and proliferate in an anchorage-independent manner, regardless of both tumor-intrinsic variables and nutrient culture conditions.Methods3D spheroids derived from lung adenocarcinoma (LUAD) and breast cancer cells were cultured in either nutrient-rich or -restricted culture conditions. A multi-omics approach, including transcriptomics, proteomics, and metabolomics, was used to explore the molecular changes underlying the transition from 2 to 3D cultures. Small interfering RNA-mediated loss of function assays were used to validate the role of the identified differentially expressed genes and proteins in H460 and HCC827 LUAD as well as in MCF7 and T47D breast cancer cell lines.ResultsWe found that the transition from 2 to 3D cultures of H460 and MCF7 cells is associated with significant changes in the expression of genes and proteins involved in metabolic reprogramming. In particular, we observed that 3D tumor spheroid growth implies the overexpression of ALDOC and ENO2 glycolytic enzymes concomitant with the enhanced consumption of glucose and fructose and the enhanced production of lactate. Transfection with siRNA against both ALDOC and ENO2 determined a significant reduction in lactate production, viability and size of 3D tumor spheroids produced by H460, HCC827, MCF7, and T47D cell lines.ConclusionsOur results show that anchorage-independent survival and growth of cancer cells are supported by changes in genes and proteins that drive glucose metabolism towards an enhanced lactate production. Notably, this finding is valid for all lung and breast cancer cell lines we have analyzed in different nutrient environmental conditions. broader Validation of this mechanism in other cancer cells of different origin will be necessary to broaden the role of ALDOC and ENO2 to other tumor types. Future in vivo studies will be necessary to assess the role of ALDOC and ENO2 in cancer metastasis.

High‑risk pathological subtype associated FAM83A‑AS1 promotes malignancy and glycolysis of lung adenocarcinoma via miR‑202‑3p/HK2 axis.

According to the diverse cellular morphology, lung adenocarcinoma (LUAD) was classified into five pathological subtypes, referred to as follows: High‑risk group (micropapillary and solid), intermediate‑risk group (acinar and papillary) and low‑risk group (epidic). Nevertheless, little is known about the biological function of long non‑coding RNA (lncRNA) in the molecular determination of LUAD histologic patterns. Screening the transcriptional expression data from TCGA‑LUAD, the differentially expressed lncRNA across the divergent pathological subtypes were explored. Pan‑cancer analysis revealed the characteristic of FAM83A‑AS1, which was also confirmed in the LUAD tissues. The function of FAM83A‑AS1 was uncovered through the invitro assays. RNA immunoprecipitation and dual‑luciferase reporter assays were performed to explore the molecular mechanisms of FAM83A‑AS1. In the present study, it was identified that the expression of FAM83A‑AS1 was increased from the low‑risk group to the high, which was associated with a poorer prognosis and higher risk of recurrence. Pan‑cancer analysis revealed that FAM83A‑AS1 was positively correlated with high tumor mutational burden. Additionally, FAM83A‑AS1 promoted cell migration, invasion and growth of LUAD cancer cells. Mechanistically, FAM83A‑AS1 sponged miR‑202‑3p to regulate the expression of hexokinase II (HK2) in post‑transcription, which facilitated the malignancy and glycolysis. The present study uncovered the biological roles of FAM83A‑AS1/miR‑202‑3p/HK2 axis in regulating malignancy and glycolysis of LUAD, which provided novel avenues to addressing the determination of histologic patterns.

The Diagnostic and Prognostic Value of miR-155 in Cancers: An Updated Meta-analysis.

MicroRNA-155 has been discussed as a biomarker in cancer diagnosis and prognosis. Although relevant studies have been published, the role of microRNA-155 remains uncertain because of insufficient data. We conducted a literature search in PubMed, Embase, and Web of Science databases to obtain relevant articles and extract data to evaluate the role of microRNA-155 in cancer diagnosis and prognosis. The pooled results showed that microRNA-155 presented a remarkable diagnostic value in cancers (area under the curve = 0.90, 95% confidence interval (CI 0.87-0.92; sensitivity = 0.83, 95% CI 0.79-0.87; specificity = 0.83, 95% CI 0.80-0.86), which was maintained in the subgroups stratified by ethnicity (Asian and Caucasian), cancer types (breast cancer, lung cancer, hepatocellular carcinoma, leukemia, and pancreatic ductal adenocarcinoma), sample types (plasma, serum, tissue), and sample size (n >100 and n <100). In prognosis, a combined hazard ratio (HR) showed that microRNA-155 was significantly associated with poor overall survival (HR = 1.38, 95% CI 1.25-1.54) and recurrence-free survival (HR = 2.13, 95% CI 1.65-2.76), and was boundary significant with poor progression-free survival (HR = 1.20, 95% CI 1.00-1.44), but not significant with disease-free survival (HR = 1.14, 95% CI 0.70-1.85). Subgroup analyses in overall survival showed that microRNA-155 was associated with poor overall survival in the subgroups stratified by ethnicity and sample size. However, the significant association was maintained in cancer types subgroups of leukemia, lung cancer, and oral squamous cell carcinoma, but not in colorectal cancer, hepatocellular carcinoma, and breast cancer, and was maintained in sample types subgroups of bone marrow and tissue, but not in plasma and serum. Results from this meta-analysis demonstrated that microRNA-155 was a valuable biomarker in cancer diagnosis and prognosis.

CT radiomics model combined with clinical and radiographic features for discriminating peripheral small cell lung cancer from peripheral lung adenocarcinoma.

Exploring a non-invasive method to accurately differentiate peripheral small cell lung cancer (PSCLC) and peripheral lung adenocarcinoma (PADC) could improve clinical decision-making and prognosis. This retrospective study reviewed the clinicopathological and imaging data of lung cancer patients between October 2017 and March 2022. A total of 240 patients were enrolled in this study, including 80 cases diagnosed with PSCLC and 160 with PADC. All patients were randomized in a seven-to-three ratio into the training and validation datasets (170 vs. 70, respectively). The least absolute shrinkage and selection operator regression was employed to generate radiomics features and univariate analysis, followed by multivariate logistic regression to select significant clinical and radiographic factors to generate four models: clinical, radiomics, clinical-radiographic, and clinical-radiographic-radiomics (comprehensive). The Delong test was to compare areas under the receiver operating characteristic curves (AUCs) in the models. Five clinical-radiographic features and twenty-three selected radiomics features differed significantly in the identification of PSCLC and PADC. The clinical, radiomics, clinical-radiographic and comprehensive models demonstrated AUCs of 0.8960, 0.8356, 0.9396, and 0.9671 in the validation set, with the comprehensive model having better discernment than the clinical model (P=0.036), the radiomics model (P=0.006) and the clinical-radiographic model (P=0.049). The proposed model combining clinical data, radiographic characteristics and radiomics features could accurately distinguish PSCLC from PADC, thus providing a potential non-invasive method to help clinicians improve treatment decisions.

Surgical treatment of patients with a combined forms of pulmonary tuberculosis and lung cancer

Objective — to improve surgical treatment of patients with combined forms of pulmonary tuberculosis and non small cell lung cancer due to minimally invasive diagnostics and with the use of sterno-mediastinal surgical dissection of tissue and complete systematic bilateral lymph node dissection (CSBLND). Materials and methods. Our studies involved retrospective analysis of 101 cases of treatment of patients with stage I—II—IIIА non-small cell lung cancer (NSCLC) and pulmonary tuberculosis. A review of diagnostics and operations over the past decade were conducted. All patients underwent surgical treatment. The main group included 48 patients who underwent 16 lobectomy and 32 pneumonectomy from the sternomediastinal access. A comparative analysis of the effectiveness of the CSBLND was carried out. The comparison group included 53 patients who underwent 17 lobectomy and 36 pneumonectomy, a surgical operation for lateral thoracotomy and selective dissection of the mediastinal lymph nodes was performed. Results and discussion. The analysis of the morphological features of combined forms of pulmonary tuberculosis and NSCLC has been made in comparison groups, that were explored retrospectively. There was a trend improved survival patients combined forms of pulmonary tuberculosis and NSCLC stage I—II—IIIA, who underwent of CSBLND (p = 0.05). A statistically significant of survival of patients who underwent pneumonectomy in the mail group (n = 32) with CSBLND (p = 0.01). In a comparative analysis of the frequency and nature of complications during surgery, we found out that in general in the main group they met in 2.1 times less often than in the comparison group (p &lt; 0.05). Complications during operation in patients of the main group occurred in (11.4 ± 2.6) %, while in the comparison group — in (22.6 ± 4.2) % of cases. The analysis of data showed that patients with adenocarcinoma of lung cancer have been improvements in the performance of sterno-mediastinal surgical techniques (CSBLND) (p = 0.12). Therefore, patients with combined forms of pulmonary tuberculosis and NSCLC for suspected «jumping metastases» we recommended to carry out operations with sternotomy surgical access with full system bilateral lymph nodes dissection and radical rezection of pathologically altered lung. All this requires further development of high-tech surgical techniques in our country. Conclusions. The leading effect of pulmonary tuberculosis on the surgical treatment of patients with combined forms of tuberculosis and lung cancer has been shown in groups of comparison. The increase of 3 years survival in patients of basic groups is set, demonstrating the advantage of active diagnostical surgical tactics of stage I—II—IIIА NSCLC with used sterno-mediastinal access and the appliance of more radical CSBLND. Thus, the clinical effect of operative patients of the main groups in the immediate postoperative period was reached 95.7 % patients, in the groups comparison clinical effect be noted in 80.5 %.