Abstract 5108: Decoding tumor intrinsic and stroma-related drug resistance in EGFR mutant NSCLC

Abstract The presence of oncogenic driver mutations such as EGFR, ALK, or KRAS renders non-small cell lung adenocarcinomas sensitive to molecularly targeted therapies, however the inevitable emergence of acquired drug resistance remains an unsolved clinical problem. Osimertinib, a third-generation EGFR inhibitor that was initially developed to overcome the EGFRT790M resistance mutation, is now the standard first-line therapy. Although various mechanisms of acquired resistance to osimertinib have been identified, the specific drivers of resistance remain unexplained in over half of patients. Recent work from our group and others has suggested that cancer-associated fibroblasts may play a role in drug resistance to tyrosine kinase inhibitors (TKIs). Notably, we have observed that patient-derived cancer-associated fibroblast (PDF) cell lines established from TKI-resistant tumors display heterogeneous phenotypes with ability to rescue cancer cells from TKIs. To enable parallel discovery of both tumor cell-intrinsic and stroma-driven resistance mechanisms to osimertinib, we developed a genome-wide CRISPR sensitizer screening approach that incorporates osimertinib-resistant patient-derived EGFR-mutant NSCLC cell lines and conditioned media from matched immortalized PDFs. These studies aim to uncover intrinsic and extrinsic resistance pathways and nominate targets for next-generation therapies to overcome acquired resistance to osimertinib Citation Format: Radhika Koranne, Aimee Gleason, Emily Hensley, Xiaodong Wang, Alba Font-Tello, Brian Rabe, Fayaz Seifuddin, Eugene Drokhlyansky, Kartik Subramanian, Martino Colombo, Jason Dobson, Mavrakis J. Konstantinos, Leila Dardaei, Aaron Hata. Decoding tumor intrinsic and stroma-related drug resistance in EGFR mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5108.