The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRAS G12D -driven non-small cell lung cancer.

Introduction: KRAS ^G12C and KRAS ^G12D inhibitors represent a major translational breakthrough for non-small cell lung cancer (NSCLC) and cancer in general by directly targeting its most mutated oncoprotein. However, resistance to these small molecules has highlighted the need for rational combination partners necessitating a critical understanding of signaling downstream of KRAS mutant isoforms.
Methods: We contrasted tumor development between Kras ^G12C and Kras ^G12D genetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models of Kras ^G12C and Kras ^G12D initiation and adaptation were profiled by RNA sequencing. We also employed cell line models of established KRAS mutant NSCLC and determined therapeutic vulnerabilities through pharmacological inhibition. We analysed differences in survival outcomes for patients affected by advanced KRAS ^G12C or KRAS ^G12D -mutant NSCLC.
Results: KRAS ^G12D exhibited higher potency in vivo, manifesting as more rapid lung tumor formation and reduced survival of KRAS ^G12D GEMMs compared to KRAS ^G12C . This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRAS ^G12C oncogenicity and downstream pathway activation were comparable with KRAS ^G12D at later stages of tumorigenesis in vitro and in vivo, consistent with similar clinical outcomes in patients. Despite this, established KRAS ^G12D NSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRAS ^G12C models on the MAPK pathway. Specifically, KRAS ^G12D inhibition was enhanced by AKT inhibition in vitro and in vivo.
Conclusions: Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.
Competing Interests: Declarations Ethics approval and consent to participate For in vivo work in mice, studies were carried out in compliance with UK Home Office regulations with protocols approved by the Cancer Research UK Manchester Institute Animal Welfare and Ethical Review Advisory Body. Chicken egg experiments did not require ethical approval before as they were carried out before day 14 of develop. For patient studies, data collection protocols were approved by local governance committee. Competing interests The authors declare no competing interests.
(© 2024. The Author(s).)