Abstract 5525: YTHDF3 and RAS-ERK1/2 pathway generate a negative feedback loop to maintain phosphorylation cascade and contribute to EGFR-TKI resistance

Abstract About half of East Asian patients with lung adenocarcinoma harbor EGFR mutations, which lead to dramatic initial response to EGFR tyrosine kinase inhibitors (EGFR TKI); however, the resistance to these therapies is ultimately inevitable. Several previous studies on EGFR TKI that typically utilized genomic, epigenomic and transcriptomic data of resistant tumors from patients attributed their resistance to bypass signal activation or downstream target mutations, however, mostly failed to overcome resistance by targeting such signals. The gap between RNA and protein expression, which obscures changes in actual phosphorylation cascade, is one plausible explanation for the previous failures of multi-layer omics studies and genome-wide screening. Given that posttranslational modification contributes to this gap, N6-Methyladenosine, which is dynamically regulated and present in the mRNAs of various genes in the RAS pathway, has emerged as an intriguing target for studying its role in EGFR TKI resistance. Here, we demonstrated that the phosphorylation cascade of EGFR-RAS-ERK1/2 and YTHDF3 regulate each other and are composed of a negative feedback loop between two independent systems. We identified blocking the EGFR signal decreased the protein stability of YTHDF3 while negative regulation of YTHDF3 intensified EGFR-RAS-ERK1/2 signaling. Our findings reveal that YTHDF3 plays a critical role in modulating EGFR TKI resistance, suggesting its potential as a therapeutic target to overcome resistance in lung cancer treatment. Citation Format: Jaeik Oh, Sung-Yup Cho. YTHDF3 and RAS-ERK1/2 pathway generate a negative feedback loop to maintain phosphorylation cascade and contribute to EGFR-TKI resistance [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 5525.