Abstract 1443: The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer

Abstract Direct inhibitors of KRASG12C and more recently KRASG12D are currently under clinical evaluation and may represent the beginning of a major translational breakthrough for non-small cell lung cancer (NSCLC) and RAS addicted cancers in general, targeting the most commonly mutated oncogene in this disease. However early reports of resistance with inactive state-selective KRASG12C inhibitors have highlighted the pressing need for rational combination partners. While preclinical combination strategies to enhance KRASG12D inhibition and combat innate resistance have already been reported for pancreatic and colorectal cancer, the application of KRASG12D inhibitors alongside combination partners in KRASG12D-driven NSCLC has not been investigated. Here we compared KRASG12C- and KRASG12D-initiated lung tumorigenesis using isogenic genetically engineered mouse models and human and mouse cell models of KRASG12C and KRASG12D-driven NSCLC initiation to compare oncopotency and signaling of each subtype. We then examined whether signaling differences observed at initiation persist in established tumors. We identified that KRASG12D is more potent than KRASG12C in inducing tumor formation. This higher potency was accompanied by co-operative activation of the PI3K-AKT-mTOR signaling axis. Disruption of this pathway using either an AKT inhibitor or mTORC1-specific inhibitor (RMC-6272, a preclinical tool compound representative of the clinical candidate RMC-5552) led to a greater reduction in transformation and proliferation in a KRASG12D−driven lung initiation model compared to the KRASG12C counterpart. Although differences between these oncogenic phenotypes become less distinguishable once tumors are established, signaling dependencies and vulnerabilities are still preserved. For instance, KRASG12C lung tumor cells are relatively more susceptible to ERK and MEK inhibition, while KRASG12D lung tumor cells are more susceptible to AKT and mTORC1 inhibition. Inhibiting the PI3K-AKT-mTOR axis alongside KRASG12D inhibition (MRTX1133) induced a robust, synergistic apoptotic response in KRASG12D tumor cell lines of varying sensitivity to KRASG12D inhibition alone, highlighting a potential combinatorial approach to override intrinsic resistance to KRASG12D inhibitors. Our preclinical data identify treatment vulnerabilities and suggest patient selection strategies for combination approaches that should be i) contextualized to individual RAS mutants, and ii) tailored to their downstream signaling programs. Citation Format: William J. McDaid, Leah Wilson, Helen Adderley, Martin Baker, Joshua Searle, Timothy Budden, Amaya Viros, Mihaela Aldea, Arianna Marinello, Jacqueline Aredo, Benjamin Besse, Heather A. Wakelee, Colin R. Lindsay, Angeliki Malliri. The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1443.