Data from Co-occurring Genomic Alterations Define Major Subsets of <i>KRAS</i>-Mutant Lung Adenocarcinoma with Distinct Biology, Immune Profiles, and Therapeutic Vulnerabilities

Abstract

<div>Abstract<p>The molecular underpinnings that drive the heterogeneity of <i>KRAS</i>-mutant lung adenocarcinoma are poorly characterized. We performed an integrative analysis of genomic, transcriptomic, and proteomic data from early-stage and chemorefractory lung adenocarcinoma and identified three robust subsets of <i>KRAS</i>-mutant lung adenocarcinoma dominated, respectively, by co-occurring genetic events in <i>STK11/LKB1</i> (the KL subgroup), <i>TP53</i> (KP), and <i>CDKN2A/B</i> inactivation coupled with low expression of the NKX2-1 (TTF1) transcription factor (KC). We further revealed biologically and therapeutically relevant differences between the subgroups. KC tumors frequently exhibited mucinous histology and suppressed mTORC1 signaling. KL tumors had high rates of <i>KEAP1</i> mutational inactivation and expressed lower levels of immune markers, including PD-L1. KP tumors demonstrated higher levels of somatic mutations, inflammatory markers, immune checkpoint effector molecules, and improved relapse-free survival. Differences in drug sensitivity patterns were also observed; notably, KL cells showed increased vulnerability to HSP90-inhibitor therapy. This work provides evidence that co-occurring genomic alterations identify subgroups of <i>KRAS</i>-mutant lung adenocarcinoma with distinct biology and therapeutic vulnerabilities.</p><p><b>Significance:</b> Co-occurring genetic alterations in <i>STK11/LKB1</i>, <i>TP53</i>, and <i>CDKN2A/B</i>—the latter coupled with low TTF1 expression—define three major subgroups of <i>KRAS</i>-mutant lung adenocarcinoma with distinct biology, patterns of immune-system engagement, and therapeutic vulnerabilities. <i>Cancer Discov; 5(8); 860–77. ©2015 AACR</i>.</p><p>This article is highlighted in the In This Issue feature, p. 783</p></div>