WCLC 2025 - Posters & ePosters-EP.03.03 Tumor Heterogeneity Consisting of SCLC With RB1 Exon 19 Deletion and L718V Mutation-Positive Adenocarcinoma in EGFR-TKI Resistant Lung Cancer

EP.03.03 Tumor Heterogeneity Consisting of SCLC With RB1 Exon 19 Deletion and L718V Mutation-Positive Adenocarcinoma in EGFR-TKI Resistant Lung Cancer

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This study investigates mechanisms of resistance to osimertinib in EGFR-mutant non-small cell lung cancer (NSCLC), focusing on tumor heterogeneity involving small cell lung cancer (SCLC) transformation and EGFR secondary mutations. Researchers established patient-derived cell lines from pleural effusion and mediastinal lymph node metastases in an EGFR L858R-mutated NSCLC patient before and after osimertinib resistance.<br /><br />Key findings revealed two distinct resistance mechanisms coexisting spatially: (1) adenocarcinoma cells harboring an acquired EGFR L718V mutation and (2) SCLC transformed cells with an RB1 exon 19 deletion. Immunohistochemistry showed the SCLC-like cells (JFCR-330-5) expressed neuroendocrine markers ASCL1 and NeuroD1 but lacked YAP1 and POU2F3. RNA sequencing confirmed low EGFR expression and elevated neuroendocrine markers in SCLC cells. Whole-exome sequencing and Sanger sequencing identified a microdeletion in RB1 exon 19 specifically in the SCLC-transformed cells.<br /><br />Functionally, cells with the EGFR L858R/L718V mutation (JFCR-330-4 and JFCR-330-7) were resistant to 3rd- and 4th-generation EGFR-TKIs but remained sensitive to the 2nd-generation TKI afatinib, suggesting a potential therapeutic approach for this resistance subtype. The SCLC-transformed cells lacked the secondary EGFR L718V mutation, indicating distinct evolutionary resistance pathways within the same patient.<br /><br />In summary, this work highlights the complexity of acquired resistance to osimertinib in EGFR-mutant NSCLC, characterized by tumor heterogeneity with simultaneous SCLC transformation through RB1 exon 19 deletion and EGFR L718V mutation-driven adenocarcinoma cells. Understanding these concurrent resistance mechanisms may guide personalized treatment strategies to overcome or prevent osimertinib resistance.<br /><br />The study was conducted by a collaborative team from the Japanese Foundation for Cancer Research, Tohoku University, and the University of Tokyo, and supports the ongoing effort to elucidate and counteract resistance in targeted lung cancer therapies.

Asset Subtitle

Sho Kakuto

Meta Tag

Speaker Sho Kakuto

Topic Tumor Biology – Translational Biology

Keywords

osimertinib resistance

EGFR-mutant NSCLC

tumor heterogeneity

small cell lung cancer transformation

EGFR L718V mutation

RB1 exon 19 deletion

neuroendocrine markers

afatinib sensitivity

third and fourth generation EGFR-TKIs

patient-derived cell lines