Abstract Despite recent progress in direct KRAS inhibitors, treatment responses vary and resistance commonly develops. The emergence of recurrent genetic alterations during therapeutic pressure suggests that genotype-specific vulnerabilities critically shape drug response. Identifying factors that govern these outcomes is thus essential for optimizing the clinical utility of KRAS inhibitors. Among recurrent co-alterations, loss of liver kinase B1 (LKB1) is one of the most prevalent KRAS co-mutations in non-small cell lung cancer (NSCLC), and LKB1 mutational status has been associated with inferior outcomes across multiple therapeutic settings. In KRAS-mutant NSCLC, co-alterations such as LKB1/KEAP1 frequently define aggressive subgroups with poor prognosis, though the specific impact of LKB1 on KRAS inhibitor efficacy remains under active investigation. LKB1 encodes a master kinase that activates AMPK and suppresses mTORC1 signaling through the TSC complex, thereby coordinating metabolic, proliferative, and adaptive responses. Loss of LKB1 has been implicated in lineage plasticity and altered tumor immunogenicity, contributing to limited responses to KRAS inhibitors and PD-1/PD-L1 blockade. Prior studies also found LKB1 loss-of-function tumors exhibit heightened reliance on adaptive survival programs under targeted inhibition, suggesting that stress-responsive mechanisms may support treatment persistence in KRAS/LKB1 co-mutant cancers. To examine functional consequences of LKB1 loss, we generated genetically engineered LKB1 knockout KRAS-mutant models and evaluated drug response under KRAS inhibitor treatment. Across in vitro assays, LKB1-deficient models showed differential sensitivity to KRAS inhibition compared to control, accompanied by alterations in proliferative and adaptive phenotypes under drug exposure. These findings suggest that LKB1 loss contributes to context-dependent therapeutic persistence and that LKB1 status may inform tumor-intrinsic adaptive mechanisms to KRAS-directed therapy. Citation Format: Mikoto Kobayashi, Yi Bao, Fan Yang, Fred Li, Caleb Cheng, Yuanyuan Qiao, Arul Chinnaiyan. Investigating adaptive responses in KRAS/LKB1 co-mutant tumors 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 B035.
Kobayashi et al. (Thu,) studied this question.