Abstract Lung adenocarcinoma (LUAD) is among the leading causes of cancer-related death worldwide, with approximately one-third of patients harboring KRAS mutations. Among these, G12C is the most prevalent alteration and the first one to be directly druggable with FDA-approved drugs. Direct KRASG12C inhibitors binding the target in its inactive conformation and locking the GDP state –RAS (OFF) inhibitors– have shown early signs of clinical activity in patients with KRASG12C-mutant LUAD, but responses are short-lived and the development of resistance is inevitable. An accurate and validated understanding of the biology of KRASG12C inhibitors-resistant tumors is urgenty needed in order to design new therapeutic strategies to effectivley target resistance in this context. We developed in vitro and in vivo models of resistance to RAS (OFF) inhibitors to validate and characterize both acquired and adaptive mechanisms of therapeutic escape, as well as to test new treatment options with compounds used as single agent or in combination. Strategies to overcome resistance with the new generation of RAS (ON) inhibitors targeting the active GTP-bound form of KRAS were also investigated in patient-derived models. We propose that acquired genetic drivers rewire KRASG12C tumor cells signaling and that this rewiring is therapeutically actionable. Morover, RAS (ON) inhibitors targeting GTP-bound KRAS may be an effective alternative to treat disease relapse due to adaptive mechanisms of signal reactivation by wild-type RAS isoforms. Citation Format: Chiara Ambrogio. Signaling plasticity in pre-clinical models of resistance to KRAS inhibitors abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr IA001.
Elisa Bergaggio (2026) studied this question.