Abstract 1632: EGFR-TKIs facilitate cuproptosis via regulating SLC31A1 in cancer cells

Abstract Cuproptosis, a novel cellular demise pathway linked to copper homeostasis and copper ionophores, offers promising therapeutic avenues across diverse human ailments. However, the effectiveness of copper ionophores in cancer treatment is not that satisfactory. Tyrosine kinase inhibitors (TKIs) have revolutionized the approach to combating various types of cancer by regulating different cell death manners. In this research, we identified EGFR-TKIs and MEK-TKIs significantly sensitized cuproptosis. Our investigation delineates that the EGFR/MEK signaling cascade phosphorylates JUND, augmenting its transcriptional prowess as a key repressor of SLC31A1. Interestingly, EGFR-TKIs enhance the interaction between EGFR and SLC31A1, impeding UBE3C-mediated degradation, thereby stabilizing SLC31A1 levels. Moreover, copper binding to the extracellular domain of EGFR promotes its dimerization and downstream phosphorylation, orchestrating a protective mechanism under copper-induced stress, whereas EGFR-TKIs interrupt EGFR-SLC31A1 cascade to sensitize cuproptosis. Overall, our findings shed light on the dual roles of EGFR-TKIs and MEK-TKIs in sensitizing cuproptosis within cancer contexts through intricate transcriptional and post-transcriptional regulation of SLC31A1. The prospective combination of EGFR/MEK-TKIs with copper emerges as a promising strategy for cuproptosis-targeted therapies across multiple malignancies with or without EGFR mutation, underscoring the innovative contributions of our study. Citation Format: Xiyi Wei, Weiyu Kong, Zijie Yu, Chao Qin, Bing Yao, Zhou Yang. EGFR-TKIs facilitate cuproptosis via regulating SLC31A1 in cancer cells [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 1632.