3MO Oncogenic non-G12C KRAS mutations in KRAS G12C mutated lung adenocarcinomas in TRACERx and GENIE: A reservoir for intrinsic resistance to KRAS G12C inhibitors

Abstract

Multiple mechanisms of acquired resistance to KRAS G12C inhibitors were recently described, with on target resistance mechanisms including the emergence of in trans, oncogenic KRAS non-G12C mutations. However, no evidence exists regarding putative mechanisms of intrinsic resistance to KRAS G12C inhibitors. We hypothesized that early convergent evolution on KRAS in LUAD could lead to the co-occurrence of multiple oncogenic KRAS variants in the same patient, irrespective of KRAS G12C targeting. We analyzed patients with publicly available multi-sample sequencing data of primary lung adenocarcinomas from TRACERx and GENIE. TRACERx: among 7 patients with a KRAS G12C mutation in primary tissue samples, one had a concomitant, subclonal KRAS G12V mutation in one tissue sample (CRUK0039); both KRAS G12C and G12V mutations were present in pre-treatment ctDNA. GENIE: Among 100 patients with a KRAS G12C mutation in primary tissue samples, 42 patients had additional oncogenic KRAS mutations. KRAS variant allele frequency (VAF) was significantly higher in patients with a KRAS G12C mutation alone, both in respect to G12C and to non-G12C mutations in patients with multiple KRAS mutations (Kruskal-Wallis p=0.02, post-hoc Dunn test p<0.05 for G12C alone vs G12C+other). Tumor mutational burden (TMB) was not significantly different between patients with KRAS G12C alone and patients with multiple oncogenic KRAS mutations (Wilcoxon p=0.7).Table: 3MOGENIE LUADG12C aloneG12C+G12VG12C+G12DG12C+G12A>2 mutG12C+Q61HG12C+G13CG12C+G12SG12C+Q61LG12C+G13DG12C+G12FG12C+Q61RN58129543222111 Open table in a new tab Multiple oncogenic, non-G12C KRAS mutations are commonly found in KRAS G12C mutated primary lung adenocarcinomas, likely due to intratumor heterogeneity and convergent evolution in the early phase of tumor growth. This putative mechanism of resistance could lead to intrinsic resistance to KRAS G12C targeting through upregulation of non-G12C KRAS mutant clones. Moreover, differences in variant allele frequency could also shape sensitivity to KRAS G12C inhibitors in such populations. If validated, our findings could have significant clinical implications for patients eligible to KRAS G12 inhibitors.