Receptor Tyrosine Kinase Inhibitor Research Articles

Multifunctional liposomal complex for detection of the acquired resistance to EGFR-TKIs and synergistic anticancer phototherapy

The emergence of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) poses formidable obstacles to non-small cell lung cancer (NSCLC) therapy. Real-time monitoring of the efficacy of EGFR-TKIs to avoid invalid treatment remains a great challenge. Herein, we rationally designed a EGFR-TKI-modified liposomal complex co-loaded with a iodine-containing contrast agent ioversol (IOV) and a photosensitizer indocyanine green (ICG), namely ELIG, for simultaneous EGFR-TKI-mediated computed tomography/fluorescence dual-modal imaging to monitor drug resistance during the treatment, and combined photodynamic therapy (PDT) and photothermal therapy (PTT) to reverse drug resistance. ELIG exhibited good physicochemical properties, favorable photothermal effects, and high singlet oxygen production. ELIG can protect ICG and IOV from rapid degradation and prolong the circulation time. In addition, ELIG had a great ability to recognize drug-sensitive EGFR-mutated NSCLC cells, and could monitor the changes in the intracellular amounts of the imaging agents to detect the drug resistance and predict the efficacy during the treatments. Additionally, the heavy atom effect of IOV can increase the PDT effect of ICG obviously. With 808 nm laser irradiation, ELIG showed satisfactory anticancer effects to reverse drug resistance by the synergism of PDT and PTT in vitro and in vivo. Hence, this work holds great promise for providing a new idea and an effective strategy for predicting and managing the efficacy of EGFR-TKIs.

Abstract PO2-01-05: Neoadjuvant pyrotinib plus trastuzumab, and chemoterapy in patients with HER2-positive early breast cancer: a real-world study

Abstract Background Pyrotinib is a new oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor that targets human epidermal growth factor receptor 1 (HER1), HER2, and HER4. Previous studies have confirmed it combined with capecitabine is safe and well-tolerated in advanced breast cancer. And also PHEDRA trial had demonstrated the efficacy and safety of pyrotinib combined with trastuzumab and docetaxel neoadjuvant therapy early HER2-positive breast cancer. However, the efficacy of pyrotinib plus trastuzumab-based in real-world neoadjuvant therapy for early breast cancer is unknown. Purpose The present study aimed to explore the efficacy of pyrotinib-based in neoadjuvant therapy for early breast cancer in real-world. Method This is investigator-initiated phase 2 real-world study recruited eligible patients, aged 18–70 years with invasive carcinoma, cT2-3N0-3M0 stage, HER2-positive breast cancer. The patients received 400 mg pyrotinib orally once per day for 21 days and trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance dose) plus different standard chemotherapy, including six 21-day cycles of docetaxel (75 mg/m2) plus carboplatin (6 mg/mL/min), or four cycles of epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2) and four cycles paclitaxel (80 mg/m2). The primary endpoint was to calculate the number of patients who achieved a pathological complete response (pCR, ypT0/is, ypN0). (ChiCTR2100052892). Result The results of the 23 patients were reported, The pCR of 12 (52.2%) patients, who reached the threshold for the design, was noted. The study is ongoing. The most frequent grade 3 to 4 adverse events were diarrhea (35.6%), which all the patients received primary prevention of diarrhea, leukopenia (44.8%), and anaemia (23.7%). However, no treatment-related deaths were recorded. Conclusion Previous studies have shown the efficacy and safety of pyrotinib plus trastuzumab and docetaxel in neoadjuvant therapy of HER2-positive early breast cancer. The current trial suggests that pyrotinib plus trastuzumab-based standard chemotherapy in real-world has promising efficacy and manageable toxicity in patients with HER2-positive early breast cancer in a neoadjuvant setting, the trial is ongoing, we will enroll more patients. Citation Format: Jun Zhou, Rui Wang. Neoadjuvant pyrotinib plus trastuzumab, and chemoterapy in patients with HER2-positive early breast cancer: a real-world study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-05.

Abstract PO1-19-11: Phase 3 Study of Tucatinib or Placebo in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy for HER2+ Metastatic Breast Cancer (HER2CLIMB-05, Trial in Progress)

Abstract Background The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in patients with untreated and/or active BM (Murthy et al. NEJM 2020, Curigliano et al. Ann Oncol 2022). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 patients will be enrolled. Eligible patients will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Patients will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Patients with hormone receptor-positive disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS, time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a two-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in Austria, Chile, Greece, Italy, Japan, Poland, Portugal, Spain, the US, and several other European, APAC, and LATAM countries. This abstract was previously presented at ESMO-BC 2022, FPN (Final Publication Number): 415, by Veronique Dieras (reused with permission). Citation Format: Erika Hamilton, Junji Tsurutani, Giuseppe Curigliano, Miguel Martín, Ciara O'Sullivan, Joo Hyuk Sohn, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Véronique Diéras. Phase 3 Study of Tucatinib or Placebo in Combination With Trastuzumab and Pertuzumab as Maintenance Therapy for HER2+ Metastatic Breast Cancer (HER2CLIMB-05, Trial in Progress) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-11.

ATTLAS, IMpower151 and ORIENT-31: Dusting off IMpower150 for Post-Osimertinib in EGFR-Mutated NSCLC?

Treatment strategies for post-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in EGFR-mutant non-small cell lung cancer (NSCLC) is an ongoing challenge. Previously, the IMPRESS trial comparing platinum doublet chemotherapy with or without EGFR-TKI did not demonstrate any progression-free survival (PFS) benefit. The retrospective subgroup analysis of IMpower150 indicated that the quad regimen (carboplatin, paclitaxel, bevacizumab, atezolizumab) improved PFS and overall survival (OS) in patients with EGFR-mutant NSCLC who progressed on first-generation EGFR-TKIs. Given the retrospective nature of the analysis, the IMpower150 regimen is not approved in the US for post-EGFR-TKI treatment. Currently, osimertinib or other third-generation (3G) EGFR-TKIs is the first-line standard of care for advanced EGFR-mutant NSCLC. MARIPOSA-2 provided the first randomized trial post-osimertinib in EGFR-mutant NSCLC patients with another quad regimen (platinum, pemetrexed, lazertinib, amivantamab). The IMpower150 and MARIPOSA-2 quad regimens differ in the principle of whether to continue or even "double-down" on EGFR inhibition. Recently, three prospective randomized trials conducted in Asia offered promising results, showing that a quad regimen of doublet platinum chemotherapy plus anti-angiogenesis agent and ICI may be as efficacious as MARIPOSA-2 with a lower rate of toxicities and accounting for the PFS difference if 1L chemotherapy plus osimertinib instead of osimertinib monotherapy. In particular, the median PFS achieved by the quad regimens of ATTLAS and IMpower151 is 8.5 months. However, only 8.2% and 17.9% of the EGFR-mutant NSCLC patients who received the quad regimens progressed on 3G EGFR-TKI, respectively. Here, we discuss how the results of IMpower151 and ATTLAS may rejuvenate interest in a non-EGFR containing quad regimen as a potential post-osimertinib monotherapy treatment. Randomized trials comparing the results of these studies, including the quad regimen of MARIPOSA-2 versus the quad regimen of IMpower151/Impower150/ATTLAS in post-osimertinib (or other 3G EGFR-TKI) progression, are urgently needed.

Targeting pyruvate dehydrogenase kinase 1 overcomes EGFR C797S mutation-driven osimertinib resistance in non-small cell lung cancer

Osimertinib, a selective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), effectively targets the EGFR T790M mutant in non-small cell lung cancer (NSCLC). However, the newly identified EGFR C797S mutation confers resistance to osimertinib. In this study, we explored the role of pyruvate dehydrogenase kinase 1 (PDK1) in osimertinib resistance. Patients exhibiting osimertinib resistance initially displayed elevated PDK1 expression. Osimertinib-resistant cell lines with the EGFR C797S mutation were established using A549, NCI-H292, PC-9, and NCI-H1975 NSCLC cells for both in vitro and in vivo investigations. These EGFR C797S mutant cells exhibited heightened phosphorylation of EGFR, leading to the activation of downstream oncogenic pathways. The EGFR C797S mutation appeared to increase PDK1-driven glycolysis through the EGFR/AKT/HIF-1α axis. Combining osimertinib with the PDK1 inhibitor leelamine helped successfully overcome osimertinib resistance in allograft models. CRISPR-mediated PDK1 knockout effectively inhibited tumor formation in xenograft models. Our study established a clear link between the EGFR C797S mutation and elevated PDK1 expression, opening new avenues for the discovery of targeted therapies and improving our understanding of the roles of EGFR mutations in cancer progression.

Role of Inflammation in the Development of COVID-19 to Parkinson's Disease.

The coronavirus disease 2019 (COVID-19) can lead to neurological symptoms such as headaches, confusion, seizures, hearing loss, and loss of smell. The link between COVID-19 and Parkinson's disease (PD) is being investigated, but more research is needed for a definitive connection. Datasets GSE22491 and GSE164805 were selected to screen differentially expressed gene (DEG), and immune infiltration and gene set enrichment analysis (GSEA) of the DEG were performed. WGCNA analyzed the DEG and selected the intersection genes. Potential biological functions and signaling pathways were determined, and diagnostic genes were further screened using gene expression and receiver operating characteristic (ROC) curves. Screening and molecular docking of ibuprofen as a therapeutic target. The effectiveness of ibuprofen was verified by constructing a PD model in vitro, and constructing "COVID19-PD" signaling pathway, and exploring the role of angiotensin-converting enzyme 2 (ACE2) in PD. A total of 13 DEG were screened from the GSE36980 and GSE5281 datasets. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that the DEG were mainly associated with the hypoxia-inducible factor (HIF-1), epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance, etc. After analysis, it is found that ibuprofen alleviates PD symptoms by inhibiting the expression of nuclear factor kappa-B (NF-κB), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α). Based on signal pathway construction, the importance of ACE2 in COVID-19-induced PD has been identified. ACE2 is found to have widespread distribution in the brain. In the 1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine (MPTP)-induced ACE2-null PD mice model, more severe motor and non-motor symptoms, increased NF-κB p65 and α-synuclein (α-syn) expression with significant aggregation, decreased tyrosine hydroxylase (TH), severe neuronal loss, and neurodegenerative disorders. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection increases the risk of PD through an inflammatory environment and downregulation of ACE2, providing evidence for the molecular mechanism and targeted therapy associated with COVID-19 and PD.

Synergistic effect of canakinumab with epidermal growth factor receptor tyrosine kinase inhibitors versus with chemotherapy for non-small cell lung cancer

Synergistic effect of canakinumab with epidermal growth factor receptor tyrosine kinase inhibitors versus with chemotherapy for non-small cell lung cancer

Interstitial Pneumonitis Following Sequential Administration of Programmed Death-1/Programmed Death-Ligand1 Inhibitors and Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors For Non-Small Cell Lung Cancer: A Matched‐Pair Cohort Study Using a Nationwide Inpatient Database

BackgroundIt is unclear whether the sequential administration of programmed death (PD)-1/programmed death-ligand 1 (PD-L1) inhibitors and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is associated with the development of severe interstitial pneumonitis (IP). Patients and MethodsWe identified 69,107 eligible patients with non-small cell lung cancer (NSCLC) from a Japanese national inpatient database, who initiated EGFR-TKI therapy. The study population was divided into the PD-1/PD-L1 inhibitor and non-prior PD-1/PD-L1 groups based on PD-1/PD-L1 administration before EGFR-TKI therapy. We conducted 1:4 matched-pair cohort analyses (n = 9,725) to compare the incidence of IP and in-hospital mortality within 90 days of administration of EGFR-TKI between the two groups after adjusting for the clinical background. Furthermore, we performed subgroup analyses categorized according to the duration of prior PD-1/PD-L1 inhibitor use. ResultsIP occurred in 4.4% of patients in the matched-pair cohort. PD-1/PD-L1 inhibitor-use before EGFR-TKI therapy was significantly associated with IP (odds ratio [OR], 1.79; 95% confidence interval [CI], 1.34-2.38) and in-hospital mortality (OR, 2.10; 95% CI, 1.72-2.55). Prior PD-1/PD-L1 inhibitor use in an interval of <6 months before EGFR-TKI administration was associated with a higher risk of IP than EGFR-TKI administration without prior PD-1/PD-L1 inhibitor. In-hospital mortality was higher in patients with prior PD-1/PD-L1 inhibitor use than that in those without prior PD-1/PD-L1 inhibitor use, irrespective of the treatment duration. ConclusionSequential use of PD-1/PD-L1 inhibitors and EGFR-TKIs in patients with non-small cell lung cancer was significantly associated with IP compared to EGFR-TKIs without prior PD-1/PD-L1 inhibitor administration.

GRP78 blockade overcomes acquired resistance to EGFR-tyrosine kinase inhibitors in non-small cell lung cancer

AimsWhile significant upregulation of GRP78 has been documented in lung cancer patients, its association with resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains underexamined. Our study aimed to elucidate the functional importance of GRP78 in acquired resistance to EGFR-TKIs in non-small cell lung cancer (NSCLC) and to evaluate its potential as a therapeutic target. Main methodsImmunoblot analysis or flow cytometry was employed to assess several markers for endoplasmic reticulum (ER) stress and apoptosis. Ru(II) complex I and HA15, two known GRP78 inhibitors, were used to evaluate the functional role of GRP78. A Xenograft assay was performed to evaluate the in vivo anti-cancer effects of the GRP78 inhibitors. Key findingsWe validated a significant increase in GRP78 protein levels in HCC827-GR, H1993-GR, and H1993-ER cells. The EGFR-TKI-resistant cells overexpressing GRP78 exhibited significantly higher cell proliferation rates than did their parental counterparts. Notably, GRP78 inhibition resulted in a more profound anti-proliferative and apoptotic response via heightened ER stress and subsequent reactive oxygen species (ROS) production in EGFR-TKI-resistant cell lines compared with their parental cells. In xenograft models implanted with HCC827-GR, both Ru(II) complex I and HA15 significantly suppressed tumor growth and reduced tumor weight. Additionally, we confirmed that GRP78 plays a critical role in the proliferation of H1975, an EGFR-TKI-resistant T790M-mutant cell line, relative to other NSCLC cell lines. SignificanceOur findings strongly support targeting of GRP78 as a promising therapeutic strategy for NSCLC patients with acquired resistance to EGFR-TKIs.

The Impact of Inadequate Exposure to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors on the Development of Resistance in Non-Small-Cell Lung Cancer Cells.

Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients treated with EGFR-tyrosine kinase inhibitors (TKIs) inevitably develop resistance through several biological mechanisms. However, little is known on the molecular mechanisms underlying acquired resistance to suboptimal EGFR-TKI doses, due to pharmacodynamics leading to inadequate drug exposure. To evaluate the effects of suboptimal EGFR-TKI exposure on resistance in NSCLC, we obtained HCC827 and PC9 cell lines resistant to suboptimal fixed and intermittent doses of gefitinib and compared them to cells exposed to higher doses of the drug. We analyzed the differences in terms of EGFR signaling activation and the expression of epithelial-mesenchymal transition (EMT) markers, whole transcriptomes byRNA sequencing, and cell motility. We observed that the exposure to low doses of gefitinib more frequently induced a partial EMT associated with an induced migratory ability, and an enhanced transcription of cancer stem cell markers, particularly in the HCC827 gefitinib-resistant cells. Finally, the HCC827 gefitinib-resistant cells showed increased secretion of the EMT inducer transforming growth factor (TGF)-β1, whose inhibition was able to partially restore gefitinib sensitivity. These data provide evidence that different levels of exposure to EGFR-TKIs in tumor masses might promote different mechanisms of acquired resistance.

Computational modeling reveals key factors driving treatment-free remission in chronic myeloid leukemia patients

Patients with chronic myeloid leukemia (CML) who receive tyrosine kinase inhibitors (TKIs) have been known to achieve treatment-free remission (TFR) upon discontinuing treatment. However, the underlying mechanisms of this phenomenon remain incompletely understood. This study aims to elucidate the mechanism of TFR in CML patients, focusing on the feedback interaction between leukemia stem cells and the bone marrow microenvironment. We have developed a mathematical model to explore the interplay between leukemia stem cells and the bone marrow microenvironment, allowing for the simulation of CML progression dynamics. Our proposed model reveals a dichotomous response following TKI discontinuation, with two distinct patient groups emerging: one prone to early molecular relapse and the other capable of achieving long-term TFR after treatment cessation. This finding aligns with clinical observations and underscores the essential role of feedback interaction between leukemic cells and the tumor microenvironment in sustaining TFR. Notably, we have shown that the ratio of leukemia cells in peripheral blood (PBLC) and the tumor microenvironment (TME) index can be a valuable predictive tool for identifying patients likely to achieve TFR after discontinuing treatment. This study provides fresh insights into the mechanism of TFR in CML patients and underscores the significance of microenvironmental control in achieving TFR.

Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery.

Monoclonal antibody-based immunotherapy targeting tumor antigens is now a mainstay of cancer treatment. One of the clinically relevant mechanisms of action of the antibodies is antibody-dependent cellular cytotoxicity (ADCC), where the antibody binds to the cancer cells and engages the cellular component of the immune system, e.g., natural killer (NK) cells, to kill the tumor cells. The effectiveness of these therapies could be improved by identifying adjuvant compounds that increase the sensitivity of the cancer cells or the potency of the immune cells. In addition, undiscovered drug interactions in cancer patients co-medicated for previous conditions or cancer-associated symptoms may determine the success of the antibody therapy; therefore, such unwanted drug interactions need to be eliminated. With these goals in mind, we created a cancer ADCC model and describe here a simple protocol to find ADCC-modulating drugs. Since 3D models such as cancer cell spheroids are superior to 2D cultures in predicting in vivo responses of tumors to anticancer therapies, spheroid co-cultures of EGFP-expressing HER2+ JIMT-1 breast cancer cells and the NK92.CD16 cell lines were set up and induced with Trastuzumab, a monoclonal antibody clinically approved against HER2-positive breast cancer. JIMT-1 spheroids were allowed to form in cell-repellent U-bottom 96-well plates. On day 3, NK cells and Trastuzumab were added. The spheroids were then stained with Annexin V-Alexa 647 to measure apoptotic cell death, which was quantitated in the peripheral zone of the spheroids with an automated microscope. The applicability of our assay to identify ADCC-modulating molecules is demonstrated by showing that Sunitinib, a receptor tyrosine kinase inhibitor approved by the FDA against metastatic cancer, almost completely abolishes ADCC. The generation of the spheroids and image acquisition and analysis pipelines are compatible with high-throughput screening for ADCC-modulating compounds in cancer cell spheroids.

Tanshinone IIA acts as a regulator of lipogenesis to overcome osimertinib acquired resistance in lung cancer

Osimertinib is a novel epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), acting as the first-line medicine for advanced EGFR-mutated NSCLC. Recently, the acquired resistance to osimertinib brings great challenges to the advanced treatment. Therefore, it is in urgent need to find effective strategy to overcome osimertinib acquired resistance. Here, we demonstrated that SREBP pathway-driven lipogenesis was a key mediator to promote osimertinib acquired resistance, and firstly found Tanshinone IIA (Tan IIA), a natural pharmacologically active constituent isolated from Salvia miltiorrhiza, could overcome osimertinib-acquired resistance in vitro and in vivo via inhibiting SREBP pathway-mediated lipid lipogenesis by using LC-MS based cellular lipidomics analysis, quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, flow cytometry, small interfering RNAs transfection, and membrane fluidity assay et al. The results showed that SREBP1/2-driven lipogenesis was highly activated in osimertinib acquired resistant NSCLC cells, while knockdown or inhibition of SREBP1/2 could restore the sensitivity of NSCLC to osimertinib via altered the proportion of saturated phospholipids and unsaturated phospholipids in osimertinib acquired-resistant cells. Furthermore, Tanshinone IIA (Tan IIA) could reverse the acquired resistance to osimertinib in lung cancer. Mechanically, Tan IIA inhibited SREBP signaling mediated lipogenesis, changed the profiles of saturated phospholipids and unsaturated phospholipids, and thus promoted osimertinib acquired resistant cancer cells to be attacked by oxidative stress-induced damage and reduce the cell membrane fluidity. The reversal effect of Tan IIA on osimertinib acquired resistant NSCLC cells was also confirmed in vivo, which is helpful for the development of strategies to reverse osimertinib acquired resistance.

Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer

Ovarian clear cell carcinoma (OCCC) is a gynecological cancer with a dismal prognosis; however, the mechanism underlying OCCC chemoresistance is not well understood. To explore the intracellular networks associated with the chemoresistance, we analyze surgical specimens by performing integrative analyses that combine single-cell analyses and spatial transcriptomics. We find that a chemoresistant OCCC subpopulation with elevated HIF activity localizes mainly in areas populated by cancer-associated fibroblasts (CAFs) with a myofibroblastic phenotype, which is corroborated by quantitative immunostaining. CAF-enhanced chemoresistance and HIF-1α induction are recapitulated in co-culture assays, which show that cancer-derived platelet-derived growth factor (PDGF) contributes to the chemoresistance and HIF-1α induction via PDGF receptor signaling in CAFs. Ripretinib is identified as an effective receptor tyrosine kinase inhibitor against CAF survival. In the co-culture system and xenograft tumors, ripretinib prevents CAF survival and suppresses OCCC proliferation in the presence of carboplatin, indicating that combination of conventional chemotherapy and CAF-targeted agents is effective against OCCC.

Abstract LT07: Signalling Inhibition by Ponatinib Disrupts Productive Alternative Lengthening of Telomeres (ALT)

Abstract Enabling replicative immortality is one prominent feature of cancer cells. To that end, cancer cells activate means to elongate their telomeres. While 85% of cancers re-express telomerase, around 15% of all cancers rely on the ALT (Alternative Lengthening of Telomeres) mechanism. Despite its frequency, no clinically approved ALT-targeted therapy exists to date. By performing anti-cancer compound library screen on isogenic cell lines and using extrachromosomal telomeric C-circles, as a bona fide marker of ALT activity, we identified a receptor tyrosine kinase inhibitor, ponatinib, that deregulates ALT mechanisms, induces telomeric dysfunction, reduced ALT- associated telomere synthesis, and targets, in vivo, ALT-positive cells. By scrutinizing the mode of action of ponatinib on ALT, we identified an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing extrachromosomal telomeric C-circle formation. Furthermore, transcriptome and interactome analyses of JUN suggested a role of JUN in DNA damage repair pathways, independently of its capacity as a transcription factor. These results were corroborated by new synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors such as triciribine and KU-60019, respectively. Overall, we identified a novel signalling pathway impacting ALT which can be targeted by a clinically approved kinase inhibitor. Citation Format: Frances Kusuma, Aishvaryaa Prabhu, Galen Tieo, Syed Moiz Ahmad, Pushkar Dakle, Wai Khang Yong, Elina Pathak, Vikas Madan, Yan Yi Jiang, Wai Leong Tam, Dennis Kappei, Peter Dröge, H. Phillip Koeffler, Maya Jeitany. Signalling Inhibition by Ponatinib Disrupts Productive Alternative Lengthening of Telomeres (ALT) [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr LT07.

Analysis of Response and Progression Patterns of Tyrosine Kinase Inhibitors in Recurrent or Metastatic Adenoid Cystic Carcinoma: A Post Hoc Analysis of Two KCSG Phase II Trials.

In this study, we evaluated 66 patients diagnosed with adenoid cystic carcinoma (ACC) enrolled in two Korean Cancer Study Group trials to investigate the response and progression patterns in recurrent and/or metastatic ACC treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). We evaluated 66 patients diagnosed with ACC who were enrolled in the Korean Cancer Study Group trials. The tumor measurements, clinical data, treatment outcomes, and progression patterns of therapy were analyzed. In the 66 patients (53 receiving axitinib and 13 receiving nintedanib), the disease control rate was 61%, and three patients achieved partial response. The median follow-up, median progression-free survival (PFS), overall survival, and 6-month PFS rate were 27.6%, 12.4%, and 18.1% months and 62.1%, respectively. Among 42 patients who experienced progression, 27 (64.3%) showed target lesion progression. Bone metastasis was an independent poor prognostic factor. Overall, most patients demonstrated stable disease with prolonged PFS; however, prominent target lesion progression occurred in some patients. Thus, PFS may capture VEGFR-TKI efficacy better than the objective response rate.

CircMYBL1 suppressed acquired resistance to osimertinib in non-small-cell lung cancer

Circular RNAs (circRNAs) play an important role in the development of acquired resistance to many anticancer drugs. We developed the Non-Small-Cell Lung Cancer (NSCLC) cell lines with acquired resistance to osimertinib, a third-generation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and evaluated the different expression profiles of circRNAs in osimertinib-sensitive and -resistant NSCLC cell lines using RNA sequencing (RNA-Seq). The expression of selected differentially expressed circRNAs was verified using quantitative real-time PCR (qRT-PCR) in paired osimertinib-sensitive and -resistant NSCLC cell lines, and in plasma samples of osimertinib-sensitive and -resistant NSCLC patients. We found that circMYBL1(has_circ_0136924) was downregulated after acquired resistance to osimertinib, inhibiting circMYBL1 expression facilitated the proliferation, migration, and invasion in osimertinib-sensitive NSCLC cells. CircMYBL1 may be a novel molecular biomarker and therapeutic target for osimertinib-resistant NSCLC.

Anlotinib may enhance the efficacy of anti-PD1 therapy by inhibiting the AKT pathway and promoting the apoptosis of CAFs in lung adenocarcinoma

Although PD-1 inhibitors have revolutionized the treatment paradigm of non-small cell lung cancer (NSCLC), their efficacy in treating NSCLC has remained unsatisfactory. Targeting cancer-associated fibroblasts (CAFs) is a potential approach for improving the immunotherapy response. Multitarget antiangiogenic tyrosine kinase receptor inhibitors (TKIs) can enhance the efficacy of PD-1 inhibitors in NSCLC patients. However, the effects and mechanisms of antiangiogenic TKIs on CAFs have not been elucidated. In this study, we first compared anlotinib with other antiangiogenic TKIs and confirmed the superior efficacy of anlotinib. Furthermore, we established NSCLC-associated CAF models and found that anlotinib impaired CAF viability and migration capacity and contributed to CAF apoptosis and cell cycle arrest in the G2/M phase. Moreover, anlotinib treatment attenuated the capacity of CAFs to recruit lung cancer cells and macrophages. Experiments in animal models suggested that anlotinib could enhance the efficacy of anti-PD1 therapy in NSCLC and affect CAF proliferation and apoptosis. Anlotinib increased the abundance of tumor-infiltrating CD8 + T cells, and PD-1 inhibitor-induced cytotoxicity to tumor cells was achieved through the transformation of the tumor microenvironment (TME) caused by anlotinib, which may partly explain the synergistic antitumor effect of anlotinib and PD-1 inhibitors. Mechanistically, anlotinib affects CAF apoptosis and cell viability at least in part by inhibiting the AKT pathway. In conclusion, our study suggested that anlotinib could regulate the TME, inhibit the AKT pathway and promote CAF apoptosis, providing new insights into the antitumor effect of anlotinib and improving the efficacy of immunotherapy.

A comprehensive clinical evaluation of HER2-TKIs in patients with previously treated HER2-positive metastatic breast cancer.

Human epidermal growth factor receptor 2-tyrosine kinase inhibitors (HER2-TKIs) have been extensively utilized for treating HER2-positive metastatic breast cancer (MBC), with numerous clinical trial reports available. We aim to systematically perform a comprehensive clinical evaluation on HER2-TKIs, provide a reference for the clinical rational use of drugs, and serve for the decision-making of the national drug policy. We performed comprehensive clinical evaluation in six dimensions including safety, effectiveness, economy, suitability, accessibility, and innovation through meta-analysis, literature review, drug administration websites, and other relevant medication data to analyze HER2-TKIs in treating HER2-positive MBC. For safety, the risk of ≥ grade 3 adverse events among pyrotinib, lapatinib, and neratinib is not significantly different. Furthermore, pyrotinib and neratinib were found to be higher in the risk of ≥ grade 3 diarrhea than lapatinib, however the risk could be reversed and prevented with loperamide. Regarding effectiveness and economy, pyrotinib was confirmed to have the best efficacy and cost-utility value, neratinib the second, and lapatinib the third. As regards innovation and suitability, pyrotinib showed better than other HER2-TKIs. In addition, pyrotinib received a higher recommendation than other HER2-TKIs in patients with HER2-positive MBC. The accessibility of pyrotinib was found to be the best with better urban, rural, and national affordability and lower annual treatment costs. Pyrotinib is more valuable in clinics with better safety, effectiveness, economy, suitability, accessibility, and innovation in HER2-positive MBC. This study could provide references for the clinical application of HER2-TKIs in treating HER2-positive MBC.

Use of Receptor and Non-receptor Tyrosine Kinase Inhibitors Is Associated with Lower Risk of Developing Parkinson Disease (S35.006)

Use of Receptor and Non-receptor Tyrosine Kinase Inhibitors Is Associated with Lower Risk of Developing Parkinson Disease (S35.006)