The barriers and enablers to participation in oncology clinical trials for ethnically diverse communities

Abstract

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.<br />