Author:
McDaid W. J.,Wilson L.,Adderley H.,Baker M. J.,Searle J.,Ginn L.,Budden T.,Aldea M.,Marinello A.,Aredo J.,Viros A.,Besse B.,Wakelee H. A.,Blackhall F.,Lindsay C. R.,Malliri A.
Abstract
AbstractIntroductionKRASG12Cand KRASG12Dinhibitors 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.MethodsWe contrasted tumor development betweenKrasG12CandKrasG12Dgenetically engineered mouse models (GEMMs). To corroborate findings and determine mutant subtype-specific dependencies, isogenic models ofKrasG12CandKrasG12Dinitiation 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 advancedKRASG12CorKRASG12D-mutant NSCLC.ResultsKRASG12Dexhibited higher potencyin vivo, manifesting as more rapid lung tumor formation and reduced survival of KRASG12DGEMMs compared to KRASG12C. This increased potency, recapitulated in an isogenic initiation model, was associated with enhanced PI3K-AKT-mTOR signaling. However, KRASG12Concogenicity and downstream pathway activation were comparable with KRASG12Dat later stages of tumorigenesisin vitroandin vivo, consistent with similar clinical outcomes in patients. Despite this, established KRASG12DNSCLC models depended more on the PI3K-AKT-mTOR pathway, while KRASG12Cmodels on the MAPK pathway. Specifically, KRASG12Dinhibition was synergistically enhanced by AKT inhibition.ConclusionsOur 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.
Publisher
Cold Spring Harbor Laboratory