BACKGROUND: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a major obstacle in the treatment of lung adenocarcinoma (LUAD), yet the underlying mechanisms are incompletely understood. METHODS: This study investigated the role of the STRIP2-IGF2BP3 axis in TKI resistance. In vitro and in vivo experiments were performed to evaluate the effect of this axis on TKI sensitivity, the mechanism by which it regulates Twist1 stability, and the prognostic relevance of these markers in LUAD tissue samples. RESULTS: STRIP2 was upregulated in TKI-resistant patient samples and cells. Knockdown of STRIP2 markedly restored EGFR-TKIs sensitivity both in vitro and in vivo. Mechanistically, STRIP2 cooperated with IGF2BP3 to drive acquired resistance by enhancing m6A modification of Twist1 and stabilizing Twist1 in an IGF2BP3-dependent manner. CONCLUSIONS: These findings highlight that the STRIP2-IGF2BP3-Twist1 axis, which mediates acquired resistance to EGFR-TKIs, represents a potential therapeutic target for LUAD patients.
Zhang et al. (Fri,) studied this question.