Abstract 5981: Over 200! The largest BaF3-EGFR engineering cell lines collection, a useful platform for novel drug discovery

Abstract The epidermal growth factor receptor (EGFR) is a cell-surface receptor tyrosine kinase that belongs to the ERBB family, which includes HER1 (EGFR), HER2, HER3, and HER4. Each of these receptors has three key layers: an input layer, a signal-processing core, and an output layer. EGFR is activated primarily through ligand binding, with ligands such as EGF, TGF-alpha, HB-EGF, AR, EPR, BTC, and epigen. However, mutations or overexpression of EGFR can lead to ligand-independent activation. Once activated, EGFR triggers various downstream signaling pathways, such as PI3K-AKT, JAK-STAT, RAS-MEK/ERK, and PLC-gamma-PKC, which enhance cell proliferation, survival, and resistance to cell death.The overexpression or increased activity of EGFR is linked to several cancers, including non-small cell lung cancer (NSCLC), colon cancer, head and neck cancer (HNC), pancreatic cancer, breast cancer, and brain cancer. Recognizing EGFR as a driver gene has accelerated the development of targeted anticancer therapies, such as monoclonal anti-EGFR antibodies (cetuximab, panitumumab) and small molecule receptor tyrosine kinase inhibitors (TKIs). The first generation of EGFR TKIs, like gefitinib and erlotinib, specifically target mutations such as L858R and exon 19 deletions. To address resistance to these early inhibitors, second-generation EGFR TKIs (afatinib, dacomitinib) were developed. The EGFR T790M mutation is a major mechanism of resistance to both first and second-generation TKIs. Osimertinib, a third-generation TKI, was approved for use in EGFR-mutated NSCLC following the failure of first- and second-generation TKIs, although the EGFR C797S mutation limits its effectiveness. Fourth-generation EGFR TKIs, including BLU-945 and BBT-176, are under clinical evaluation but are not yet approved.We have created more than 200 Ba/F3-EGFR engineered cell lines, making this the largest in vitro and in vivo platform for drug discovery with the widest range of mutant cells. These cell lines include almost all clinically significant EGFR mutations, such as common mutations like L858R and exon 19 deletions, as well as rare mutations like L861Q, S768I, and combinations of mutations like L858R/T790M, Del19/T790M, and triple mutations. These Ba/F3-EGFR engineered cell lines are valuable tools for developing and assessing next-generation EGFR inhibitors and for studying newly acquired resistance mutations in EGFR. Citation Format: Yao Tang, Guoqian Wang, Tingduo Lv, Jingxiao Xu, Yao Peng, Jinying Ning, Feng Hao. Over 200! The largest BaF3-EGFR engineering cell lines collection, a useful platform for novel drug discovery [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 5981.