Data from Comparative Analysis and Isoform-Specific Therapeutic Vulnerabilities of <i>KRAS</i> Mutations in Non–Small Cell Lung Cancer

Abstract

<div>AbstractPurpose:<p>Activating missense mutations of <i>KRAS</i> are the most frequent oncogenic driver events in lung adenocarcinoma (LUAD). However, KRAS isoforms are highly heterogeneous, and data on the potential isoform-dependent therapeutic vulnerabilities are still lacking.</p>Experimental Design:<p>We developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability of KRAS-mutant isoforms. In parallel, we analyzed clinicopathologic and genomic data from 3,560 patients with non–small cell lung cancer (NSCLC) to survey allele-specific features associated with oncogenic KRAS mutations.</p>Results:<p>In isogenic cell lines expressing different mutant KRAS isoforms, we identified isoform-specific biochemical, biological, and oncogenic properties both <i>in vitro</i> and <i>in vivo</i>. These exclusive features correlated with different therapeutic responses to MEK inhibitors, with <i>KRAS</i> G12C and Q61H mutants being more sensitive compared with other isoforms. <i>In vivo</i>, combined KRAS G12C and MEK inhibition was more effective than either drug alone. Among patients with NSCLCs that underwent comprehensive tumor genomic profiling, <i>STK11</i> and <i>ATM</i> mutations were significantly enriched among tumors harboring <i>KRAS</i> G12C, G12A, and G12V mutations. <i>KEAP1</i> mutation was significantly enriched among <i>KRAS</i> G12C and <i>KRAS</i> G13X LUADs. <i>KRAS</i> G13X-mutated tumors had the highest frequency of concurrent <i>STK11</i> and <i>KEAP1</i> mutations. Transcriptomic profiling revealed unique patterns of gene expression in each KRAS isoform, compared with <i>KRAS</i> wild-type tumors.</p>Conclusions:<p>This study demonstrates that KRAS isoforms are highly heterogeneous in terms of concurrent genomic alterations and gene-expression profiles, and that stratification based on <i>KRAS</i> alleles should be considered in the design of future clinical trials.</p></div>