EGFR-mutant Non-small Cell Lung Research Articles

Abstract 3220: Osimertinib-induced epigenetic and transcriptional reprogramming drives a BRD4-POUF-PDGFRB-YAP-EMT axis of resistance in NSCLC

Abstract Acquired resistance to Osimertinib continues to pose a major limitation to achieving durable therapeutic responses in EGFR mutant non-small cell lung cancer (NSCLC). While multiple actionable genetic mutations have been identified as the underlying molecular basis of resistance, a genomic mechanism cannot be identified in >50% of Osimertinib resistant tumors and thus an effective combinatorial treatment strategy cannot be deployed for these patients. Recently, we identified YAP/TEAD activation and ERK1/2 reactivation as two major non-mutational counter-regulatory pathways that diminish the efficacy of Osimertinib, promoting establishment of the drug tolerant persister (DTP) and resistant states. Moreover, it is well known that cancer cells escape tyrosine kinase inhibitor (TKI) therapy by developing dependence on alternate, non-mutated receptor tyrosine kinases (RTKs) through a treatment-induced “RTK switch” phenomenon. The link however between alternate RTK signaling and YAP/TEAD/ERK1/2 has never been explored in the context of Osimertinib resistance. In this study, we systemically uncover transcriptional de-repression of, and critical dependence on PDGFRβ as part of a novel “RTK switch” mechanism deployed by cells to evade Osimertinib-induced death. Genetic or pharmacologic co-inhibition of PDGFRβ renders NSCLC cells more sensitive to Osimertinib during drug naïve, DTP and resistant phases of treatment through suppression of ERK1/2 reactivation, YAP activity/nuclear translocation and YAP-mediated induction of EMT factors, SLUG and Zeb2. Importantly, compared to Osimertinib alone, co-targeting EGFR and PDGFRβ robustly suppresses tumor regrowth following treatment cessation both in vitro and in vivo which is consistent with a reduction in the DTP cell population. These data auspiciously demonstrate a two-fold utility of concomitant PDGFRβ inhibition: to enhance the initial efficacy of Osimertinib and to eliminate the DTP and resistant cells following chronic Osimertinib treatment. Further mechanistic studies from integration of ATAC-seq, CUT&RUN and RNA-seq reveal that Osimertinib induces the dynamic cooperativity of chromatin modulator BRD4 with pluripotent POU-domain transcription factors Oct-4, Pit-1 and Brn-3 at putative proximal enhancer elements, facilitating upregulation of PDGFRβ. Collectively, we demonstrate a novel treatment-induced BRD4/POUF epigenetic/transcriptional mediated “RTK switch” that involves co-opting PDGFRβ signaling to activate YAP/TEAD and ERK1/2 as a means of driving adaptive resistance to Osimertinib. These data provide compelling rationale for combined anti-EGFR and PDGFRβ targeted therapy to improve patient outcomes. Citation Format: Antja-Voy Hartley, Caitlyn Weston, Simon Baldacci, William Feng, Mustafa Al-Dulaimi, Claudia Gentile, Matthew Booker, Michael Tolstorokuv, Cigall Kadoch, Pasi Janne. Osimertinib-induced epigenetic and transcriptional reprogramming drives a BRD4-POUF-PDGFRB-YAP-EMT axis of resistance in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3220.

Abstract 1914: Amivantamab efficacy in wildtype EGFR NSCLC tumors correlates with levels of ligand expression

Abstract Amivantamab (RYBREVANT™) is an FDA-approved, low-fucose IgG1 bispecific antibody targeting EGF and Met receptor tyrosine kinases, with proven clinical activity against EGFR mutant non-small cell lung cancer (NSCLC). Preclinical studies demonstrated that three context-dependent mechanisms of action (MOA) contribute to amivantamab efficacy: immune cell-mediated killing by antibody-dependent cellular cytotoxicity and trogocytosis, receptor internalization and degradation, and inhibition of ligand binding to both EGF and Met receptors. In tumors lacking known cancer-driver genetic aberrations, ligand binding to wildtype EGFR (EGFRWT) and/or MetWT may activate downstream signaling pathways, inducing pro-tumorigenic processes. Among the EGFR ligands, we demonstrated that amphiregulin (AREG) is highly expressed in EGFRWT NSCLC primary tumors, with significantly higher circulating protein levels in NSCLC patients than in healthy volunteers, and induces EGFR phosphorylation, promoting downstream signaling and increasing cell proliferation. Importantly, treatment of AREG-stimulated EGFRWT cells/tumors with amivantamab, or an AREG-targeting antibody, inhibits ligand-induced signaling and cell/tumor proliferation/growth. Across 10 EGFRWT NSCLC patient-derived xenograft mouse models, amivantamab efficacy correlated with AREG RNA levels, suggesting AREG as a potential predictive marker for amivantamab activity in this population. Interestingly, in these xenograft models, amivantamab anti-tumor activity was independent of amivantamab's Fc engagement with immune cells, suggesting that, in this context, the amivantamab’s ligand-blocking function is sufficient for its efficacy. Juxtaposedly, we previously demonstrated that low fucose amivantamab, active Fc domain, was necessary for maximal anti-tumor activity against tumors with EGFR or Met activating mutations. Altogether, these results demonstrated amivantamab context-dependent MOA for efficacy. In conclusion, these data 1) highlight EGFR ligand AREG as a driver of tumor growth in some EGFRWT NSCLC models, 2) illustrate the preclinical efficacy of amivantamab in ligand-driven EGFRWT NSCLC, and 3) identify AREG as a potential predictive biomarker for amivantamab against anti-EGFRWT therapies. Citation Format: Ricardo Rivera-Soto, Benjamin Henley, Marian Pulgar, Stacey Lehman-Tenuto, Himanshu Gupta, Megan Weindorfer, Smruthi Vijayaraghavan, Tsun-Wen Yao, Sylvie Laquerre, Sheri Moores. Amivantamab efficacy in wildtype EGFR NSCLC tumors correlates with levels of ligand expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1914.

Abstract 4756: Targeting DNA topoisomerase II to manage acquired resistance to third generation EGFR tyrosine kinase inhibitors in the treatment of EGFR mutant NSCLC

Abstract Development of effective strategies to manage the inevitable acquired resistance to osimertinib, a 3rd generation EGFR inhibitor with proven clinical efficacy in prolonging survival of patients with EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC), is an urgent and critical area of unmet need in the clinic. Effort toward this direction led us to find that the DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide (VP-16), but not other chemotherapeutic agents, synergistically decreased the survival of osimertinib-resistant cell lines when combined with osimertinib. The combination of osimertinib with either doxorubcin or VP-16 effectively induced DNA damage and apoptosis in osimertinib-resistant cells, suppressed the growth of osimertinib-resistant tumors, and delayed the emergence of acquired resistance to osimertinib. Mechanistic studies found that osimertinib as well other EGFR-TKIs effectively decreased Topo IIα levels in EGFRm NSCLC cells by facilitating its proteasomal degradation and induced DNA damage; these effects were lost in cell lines with osimertinib acquired resistance that possessed elevated basal levels of Topo IIα. In the majority of EGFRm NSCLC tissues relapsed from EGFR-TKI treatment, Topo IIα levels were substantially increased. Enforced expression of ectopic TOP2A genes in sensitive EGFRm NSCLC cells conferred resistance to osimertinib in inducing DNA damage and apoptosis, whereas knockdown of TOP2A in osimertinib-resistant cell lines restored their responses to undergo osimertinib-induced DNA damage and apoptosis. Together, these results reveal a previously undiscovered essential role of Topo IIα modulation in regulating the responses of EGFRm NSCLC cells to osimertinib, providing scientific rationale for targeting Topo II to manage acquired resistance to osimertinib and possibly other third generation EGFR-TKIs, thus warranting clinical validation of this strategy. (This study was supported by NIH/NCI R01 CA223220 and UG1 CA233259 and Emory Winship Cancer Institute lung cancer research pilot funds). Citation Format: Zhen Chen, Karin A. Vallega, Dongsheng Wang, Zihan Quan, Songqing Fan, Qiming Wang, Ticiana A. Leal, Suresh S. Ramalingam, Shi-Yong Sun. Targeting DNA topoisomerase II to manage acquired resistance to third generation EGFR tyrosine kinase inhibitors in the treatment of EGFR mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4756.

DNA topoisomerase II inhibition potentiates osimertinib's therapeutic efficacy in EGFR-mutant non-small cell lung cancer models.

Development of effective strategies to manage the inevitable acquired resistance to osimertinib, a third-generation EGFR inhibitor for the treatment of EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), is urgently needed. This study reports that DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide, synergistically decreased cell survival, with enhanced induction of DNA damage and apoptosis in osimertinib-resistant cells; suppressed the growth of osimertinib-resistant tumors; and delayed the emergence of osimertinib-acquired resistance. Mechanistically, osimertinib decreased Topo IIα levels in EGFRm NSCLC cells by facilitating FBXW7-mediated proteasomal degradation, resulting in induction of DNA damage; these effects were lost in osimertinib-resistant cell lines that possess elevated levels of Topo IIα. Increased Topo IIα levels were also detected in the majority of tissue samples from patients with NSCLC after relapse from EGFR tyrosine kinase inhibitor treatment. Enforced expression of an ectopic TOP2A gene in sensitive EGFRm NSCLC cells conferred resistance to osimertinib, whereas knockdown of TOP2A in osimertinib-resistant cell lines restored their susceptibility to osimertinib-induced DNA damage and apoptosis. Together, these results reveal an essential role of Topo IIα inhibition in mediating the therapeutic efficacy of osimertinib against EGFRm NSCLC, providing scientific rationale for targeting Topo II to manage acquired resistance to osimertinib.

The Role of miR-29a and miR-143 on the Anti-apoptotic MCL-1/cIAP-2 Genes Expression in EGFR Mutated Non-small Cell Lung Carcinoma Patients.

The survival rate of lung cancer is low due to the high frequency of drug resistance in patients with mutations in the driver genes. Overexpression of anti-apoptotic genes is one of the most prominent features of tumor drug resistance. EGFR signaling induces the expression of anti-apoptotic genes. Also, microRNAs (miRNAs) have a critical role in regulating biological functions such as apoptosis; a process mostly eluded in cancer progression. The mutation screening was performed on one thousand non-small cell lung carcinoma patients to enroll clinical samples in this study. Bioinformatics analysis predicted that miRNAs (miR-29a, miR-143) might regulate MCL-1 and cIAP-2 expression. We investigated the expression of MCL-1, cIAP-2, miR-29a, and miR-143 encoding genes in adenocarcinoma patients with or without EGFR mutations before treatment. The potential role of miR-29a and miR-143 on gene expression was evaluated by overexpression and luciferase assays in HEK-293T cells. EGFR mutations were found in 262 patients (26.2%) with a greater incidence in females (36.23% vs. 20.37%, P = 0.001). The expression levels of MCL-1 and cIAP-2 genes in patients with mutated EGFR were higher than those of wild-type EGFR. In contrast, compared to those of patients with wild-type EGFR, the expression levels of miR-29a and miR-143 were lower in the patients carrying EGFR mutations. In cell culture, overexpression of miR-29a and miR-143 significantly downregulated the expression of MCL-1 and cIAP-2. Dual-luciferase reporter experiments confirmed that miR-29a and miR-143 target MCL-1 and cIAP-2 mRNAs, respectively. Our results suggest that upregulation of EGFR signaling in lung cancer cells may increase anti-apoptotic MCL-1 and cIAP-2 gene expression, possibly through downregulation of miR-29a-3p and miR-143-3p.

Clinicopathological Characteristics and Real-life Data of Patients Receiving Tyrosine Kinase Inhibitor in Metastatic EGFR Mutant Non-small Cell Lung Carcinoma

Clinicopathological Characteristics and Real-life Data of Patients Receiving Tyrosine Kinase Inhibitor in Metastatic EGFR Mutant Non-small Cell Lung Carcinoma

EP12.01-10 Predictors of Poor Outcomes Among Patients Receiving 1st-Line Osimertinib for Advanced EGFR Mutated Non-Small Cell Lung Cancer

EP12.01-10 Predictors of Poor Outcomes Among Patients Receiving 1st-Line Osimertinib for Advanced EGFR Mutated Non-Small Cell Lung Cancer

EP12.01-41 Osimertinib beyond Progression in Patients with EGFR Mutated Non-small Cell Lung Cancer (NSCLC) Receiving Frontline Osimertinib

EP12.01-41 Osimertinib beyond Progression in Patients with EGFR Mutated Non-small Cell Lung Cancer (NSCLC) Receiving Frontline Osimertinib

WS02.12 Aumolertinib Plus Anlotinib as 1st-Line Treatment for EGFR Mutant Non-Small Cell Lung Cancer: A Phase II Trial (ALWAYS)

WS02.12 Aumolertinib Plus Anlotinib as 1st-Line Treatment for EGFR Mutant Non-Small Cell Lung Cancer: A Phase II Trial (ALWAYS)

P2.09-32 Aumolertinib Plus Anlotinib as 1st-Line Treatment for EGFR Mutant Non-Small Cell Lung Cancer: A Phase II Trial (ALWAYS)

P2.09-32 Aumolertinib Plus Anlotinib as 1st-Line Treatment for EGFR Mutant Non-Small Cell Lung Cancer: A Phase II Trial (ALWAYS)

1510TiP Efficacy study of osimertinib in treatment-naïve patients with EGFR mutant non-small cell lung cancer (NSCLC) according to TP53 mutational status (TEMPLE-2/NCT05785208)

1510TiP Efficacy study of osimertinib in treatment-naïve patients with EGFR mutant non-small cell lung cancer (NSCLC) according to TP53 mutational status (TEMPLE-2/NCT05785208)

2207P Mainstream germline genetic testing in routine oncological care of EGFR mutant non-small cell lung cancer in the United Kingdom

2207P Mainstream germline genetic testing in routine oncological care of EGFR mutant non-small cell lung cancer in the United Kingdom

Discovery of potent and effective inhibitors containing sulfoxide structures targeting EML4-ALK rearrangement and EGFR mutant non-small cell lung cancer

For non-small cell lung cancer patients with dual mutations in EGFR and ALK, there are currently no effective therapies. Consequently, novel EGFR/ALK dual-target inhibitors are urgently needed for the treatment of NSCLC. Here, we designed a series of highly effective small molecule dual inhibitors of ALK and EGFR. The biological evaluation highlighted that most of these new compounds could effectively inhibit both ALK and EGFR in enzymatic and cellular assays. Compound (+)-8l was investigated for its antitumor properties, and it was found that (+)-8l blocked the phosphorylation of EGFR and ALK induced by ligands and inhibited phosphorylation-ERK and phosphorylation-AKT induced by ligands. Furthermore, (+)-8l also induces apoptosis and G0/G1 cell cycle arrest in cancer cells and inhibits proliferation, migration, and invasion. Notably, (+)-8l significantly suppressed tumor growth in the H1975 cell-inoculated xenograft model (20 mg/kg/d, TGI: 96.11%), PC9 cell-inoculated xenograft model (20 mg/kg/d, TGI: 96.61%) and EML4 ALK-Baf3 cell-inoculated xenograft model (30 mg/kg/d, TGI: 80.86%). These results highlight the differentiated potential of (+)-8l to inhibit ALK rearrangement and EGFR mutation in NSCLC.

Clinical analysis of the presence of comutations in patients with EGFR-mutated NSCLC.

e21001 Background: EGFR mutation is the most common treatable molecular alteration in non-small cell lung cancer (NSCLC), in particular in adenocarcinoma it can be found in 10-15% of our patients (spanish population). But the presence of other commutations in EGFR mutated tumors and its implications has not been well characterized. Methods: We selected patients diagnosed with EGFR mutation non-small cell lung carcinoma (NSCLC) from February 2021 to March 2022 from 4 hospitals in Madrid (most of them from Fundación Jimenez Diaz University Hospital). EGFR status and the presence of commutations was determined by using the AVENIO Tumor Tissue Targeted Kit (a Next Generation Sequencing test). PD-L1 status was determined by immunohistochemistry assay (22C3 pharmDx). Molecular and clinicopathological characteristics were collected and we performed a descriptive analysis of our population. Results: Of the 48 patients evaluated, 68.8% were women and 31.3% were men. 73% were ECOG 0 and 23% ECOG 1 and only 44% were non-smokers, being 18.8% smokers and 37% ex-smokers, most of them with low consumption. The 91.7% were adenocarcinomas and 8.3% were squamous carcinomas. 43.7% were PD-L1 negative and 10.4% were high expressors (PD-L1 > 50%). Of the stage at diagnosis, 60.4% were stage IV and 16.7% were stage III, with 22.9% being stage I and II. Of the Stage IV patients, 87.7% debuted as patients with high disease burden, with only 13.3% being oligometastatic (oligometastatic being understood as those with less than 5 metastases in 3 different organs, including the primary tumor). 40% of them had brain metastasis at the diagnosis. Of the mutational profile, 50% had an exon 19 deletion, 25% had an L858R mutation and the rest had infrequent mutations (12.5% amplification, 10.4% exon 20 insertion and 6.3% exon 18 mutations). In our cases, we evidence that 56.25% of the patients, analyzed by NGS, had another mutation. Of all of them the most frequent was p53 (seen in 55% of the commutated cases), being less frequent others, such as MET and APC amplification (4.2%) and others with a 2.1% (PI3K, BAP1, KRAS, ALKt or HER2 amplification). Finally, we analyzed the progression-free survival (PFS) and overall survival (OS) of commutated patients vs. non-commutated treated with Osimertinib as a first line treatment and, although it was statistically non-significant due to the small sample size (11 vs 9) and the short follow-up, a very positive trend was seen (log-rank test p = 0.055 and p = 0.136 respectively). Conclusions: With the development of NGS, the presence of other commutations besides EGFR have implications that are still unknown, but it appears that it may cause worse OS and PFS. This should be studied in larger cohorts with longer follow-up.

Circulating tumor DNA to guide furmonertinib monotherapy or combination therapy in advanced EGFR mutant non-small cell lung cancer (NSCLC): A randomized, open-label, multicenter study (FOCUS-C).

TPS9150 Background: Detection of EGFR ctDNA after several weeks EGFR-TKIs treatment was an effective method to identify prognosis of advanced EGFR mutant NSCLC patients. Patients with uncleared EGFR ctDNA had shorter progression-free survival (PFS) ( Mack PC et al; CCR 2022). However, whether they can benefit from EGFR-TKI combination therapy has not been reported. Furmonertinib (AST2818), a potent, orally bioavailable, highly brain penetrant, third generation EGFR-TKI with unique chemical structure designed to improve potency and specificity, showed superior efficacy compared with gefitinib as first-line therapy in EGFR mutant NSCLC along with an acceptable safety profile without new signals ( Shi, YK et al.; Lancet Respir Med 2022). We hypothesized that monitoring clearance of EGFR ctDNA in blood could rationally guide subsequent monotherapy or combination therapy with furmonertinib and will improve outcomes in patients with uncleared EGFR ctDNA. Methods: The FOCUS-C study is a multicenter, open-label, randomized study. Patients who are aged 18 years or older and have histologically confirmed, locally advanced or metastatic, stage IIIB, IIIC, or IV unresectable NSCLC with EGFR exon 19 deletions (19Del) or exon 21 Leu858Arg mutation (L858R) on tissue biopsy and plasma will be treated with furmonertinib. Eligible patients with uncleared EGFR 19Del or L858R ctDNA after 3 weeks furmonertinib treatment will be stratified according to EGFR mutation (19Del or L858R), central nervous system metastases (with or without) and detectable accompanying gene aberrances in plasma (with or without) and randomly assigned (2: 2: 1) to receive furmonertinib or furmonertinib plus chemotherapy (pemetrexed and carboplatin for 4 cycles followed by maintenance pemetrexed) or furmonertinib plus chemotherapy plus bevacizumab (pemetrexed, carboplatin and bevacizumab for 4 cycles followed by maintenance pemetrexed and bevacizumab) in 21-day cycles until disease progression, the occurrence of intolerable toxicities, withdrawal of consent, or other discontinuation reasons judged by the investigators. The primary endpoint is PFS between furmoneritnib plus chemotherapy versus furmonertinib alone. Secondary endpoints include PFS, objective response rate, duration of response, disease control rate, overall survival and safety. Several exploratory endpoints will also be evaluated based on ctDNA detection by next-generation sequencing (Genecast, Wuxi, China). The study is enrolling. 34 patients had been enrolled till 2nd Feb 2023. Clinical trial information: NCT05334277 .

Epithelial-mesenchymal transition is associated with osteopontin-induced EGFR‑TKI resistance in EGFR mutant non-small cell lung cancer.

Resistance restricts the long-term therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer (NSCLC) with positive EGFR mutations. The present study sought to identify the potential protein osteopontin (OPN) involved in EGFR-TKI resistance and examine its therapeutic mechanism in NSCLC. The expression of OPN in NSCLC tissues was evaluated by immunohistochemistry (IHC). Western blot (WB), quantitative real‑time polymerase chain reaction (qRT-PCR), and immunofluorescence staining were used to analyze OPN and epithelial-mesenchymal transition (EMT)-related protein expression in the PC9 and PC9 gefitinib resistance (PC9GR) cells. Enzyme-linked immunosorbent assays (ELISAs) were used to detect the secreted OPN. Cell Counting Kit-8 (CCK-8) assays and flow cytometry were used to examine the effect of OPN on the gefitinib-induced growth and death of PC9 or PC9GR cells. OPN was upregulated in the human NSCLC tissues and cells resistant to EGFR-TKIs. The overexpression of OPN inhibited EGFR-TKI-induced apoptosis and was associated with the formation of EMT. By activating the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)-EMT pathway, OPN contributed to the development of EGFR-TKI resistance. Reducing OPN expression and inhibiting PI3K/AKT signaling improved EGFR-TKI sensitivity significantly more than the use of either agent alone. This study showed that OPN increased EGFR-TKI resistance in NSCLC through the OPN-PI3K/AKT-EMT pathway. Our findings may provide a possible therapeutic target for overcoming EGFR-TKI resistance in this pathway.

Highlights from Recent Cancer Literature.

Breaking Insights| April 04 2023 Highlights from Recent Cancer Literature Author & Article Information Online ISSN: 1538-7445 Print ISSN: 0008-5472 ©2023 American Association for Cancer Research2023American Association for Cancer Research Cancer Res (2023) 83 (7): 975–976. https://doi.org/10.1158/0008-5472.CAN-83-7-BI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record April 4 2023 Citation Highlights from Recent Cancer Literature. Cancer Res 1 April 2023; 83 (7): 975–976. https://doi.org/10.1158/0008-5472.CAN-83-7-BI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Although EGFR inhibitors have high response rates in EGFR mutant non-small cell lung cancer (NSCLC), 30% of patients fail to respond. Wang and colleagues developed a histology-based digital-staining predictive model for EGFR inhibitors. Utilizing a standard hematoxylin and eosin slide, they demonstrated that tumor–tumor interactions predicted for better survival, while tumor–stroma interactions predicted for worse survival. Tumors in the “predicted benefitting group” had expression features associated with proliferation and activation of p53, while tumors in the “predicted non-benefitting group” had expression signatures associated with the HGF/MET, PI3K/AKT, and EMT pathways. Expert Commentary: The authors have developed a universally applicable predictive model for EGFR TKI efficacy, which could be widely adopted in clinical practice. Wang S, Rong R, Yang DM, Fujimoto J, Bishop JA, Yan S, et al. Features of tumor-microenvironment images predict targeted therapy survival benefit in patients with EGFR-mutant lung cancer. J Clin Invest 2023;133:e160330. doi: 10.1172/JCI160330. The tumor... You do not currently have access to this content.

20 Phase II randomized study of osimertinib (OSI) with or without local consolidative therapy (LCT) for metastatic EGFR mutant non-small cell lung cancer (NSCLC): Analysis of adverse events (AEs)

20 Phase II randomized study of osimertinib (OSI) with or without local consolidative therapy (LCT) for metastatic EGFR mutant non-small cell lung cancer (NSCLC): Analysis of adverse events (AEs)

Dysregulated expression of microRNA involved in resistance to osimertinib in EGFR mutant non-small cell lung cancer cells.

An increasing amount of evidence has confirmed that the altered expression of microRNAs (miRNAs) is critical to the mechanism underlying primary and even acquired resistance to tyrosine kinase inhibitors (TKIs). However, studies on the linkage between the altered miRNAs expression and osimertinib resistance are few, and the effect of miRNAs in this context is still unclear. In the light of this, we hypothesized that the differential expression of multiple miRNAs is the driver in the osimertinib resistance process. Thus, the aim of our study was to find differentially expressed miRNAs in non-small cell lung cancer cells resistant to osimertinib. An AZD9291(Osimertinib)-resistant cell line model was constructed, and the differential miRNAs between epidermal growth factor receptor (EGFR)-sensitive cell lines A549 and H1975 and the corresponding drug-resistant cell lines were identified via biosynthesis analysis. In the A549 osimertinib-resistant cell line, 93 miRNAs were upregulated and 94 miRNAs were downregulated. In the H1975 osimertinib-resistant cell line, 124 miRNAs were upregulated and 53 miRNAs were downregulated. Finally, 7 significantly different miRNAs were screened using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. This study on the mechanism of target therapy in lung cancer systematically and comprehensively examined the miRNAs involved in osimertinib resistance. It was found that miR-708-5p, miR-708-3p, miR-10395-3p, miR-7704 miR-34a-5p, miR-19b-1-5p, and miR-219a-5p may play key roles in osimertinib resistance.

Clinical efficacy and prognosis analysis of treatment regimens for EGFR mutant non-small cell lung cancer and brain metastasis: a retrospective study

BackgroundThe aims of the study were to evaluate potential differences among first-line treatment for EGFR mutant (m+) non-small cell lung cancer (NSCLC) patients with brain metastasis in China and to identify the factors influencing survival outcomes.MethodsIn this retrospective study, 172 EGFRm + patients with advanced NSCLC who received a 1st generation EGFR tyrosine kinase inhibitor (TKI) were divided into 4 groups: A, EGFR-TKI (n = 84); B, EGFR-TKI + pemetrexed + cisplatin/carboplatin chemotherapy (CT) (n = 55); C, EGFR-TKI + bevacizumab (n = 15); and D, EGFR-TKI + pemetrexed + cisplatin/carboplatin CT + bevacizumab (n = 18). Intracranial and extracranial progression-free survival (PFS), the overall survival (OS), objective remission rates (ORRs) and adverse events were analyzed.ResultsIntracranial PFS of groups C + D was longer than for groups A + B (18.9 m vs. 11.0 m, P = 0.027). Extracranial PFS were longer in group B in comparison with group A (13.0 m vs. 11.5 m, P = 0.039) and in groups C + D compared to groups A + B (18.9 m vs. 11.9 m, P = 0.008). Median OS in groups A and B were 27.9 m and 24.4 m, respectively, while groups C and D have not yet achieved median OS. Significant difference was found in intracranial ORR between groups A + B vs. C + D (31.0% vs. 65.2%, P = 0.002). Most patients suffered grade 1–2 treatment-related adverse events, which were relieved soon after symptomatic treatment.ConclusionsFirst-generation EGFR-TKI + bevacizumab treatment outperformed other regimens in EGFRm + NSCLC patients with brain metastasis. The therapy improved the control and delayed progression of intracranial lesions and prolonged survival times.