Data from <i>ATM</i> Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC

Abstract

<div>AbstractPurpose:<p><i>Ataxia-telangiectasia mutated</i> (<i>ATM</i>) is the most frequently mutated DNA damage repair gene in non–small cell lung cancer (NSCLC). However, the molecular correlates of <i>ATM</i> mutations and their clinical implications have not been fully elucidated.</p>Experimental Design:<p>Clinicopathologic and genomic data from 26,587 patients with NSCLC from MD Anderson, public databases, and a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB) were used to assess the co-mutation landscape, protein expression, and mutational processes in <i>ATM</i>-mutant tumors. We used the CGDB to evaluate <i>ATM</i>-associated outcomes in patients treated with immune checkpoint inhibitors (ICI) with or without chemotherapy, and assessed the effect of <i>ATM</i> loss on STING signaling and chemotherapy sensitivity in preclinical models.</p>Results:<p>Nonsynonymous mutations in <i>ATM</i> were observed in 11.2% of samples (2,980/26,587) and were significantly associated with mutations in <i>KRAS</i>, but mutually exclusive with <i>EGFR</i> (<i>q</i> < 0.1). <i>KRAS</i> mutational status constrained the <i>ATM</i> co-mutation landscape, with strong mutual exclusivity with <i>TP53</i> and <i>KEAP1</i> within <i>KRAS</i>-mutated samples. Those <i>ATM</i> mutations that co-occurred with <i>TP53</i> were more likely to be missense mutations and associate with high mutational burden, suggestive of non-functional passenger mutations. In the CGDB cohort, dysfunctional <i>ATM</i> mutations associated with improved OS only in patients treated with ICI-chemotherapy, and not ICI alone. <i>In vitro</i> analyses demonstrated enhanced upregulation of STING signaling in ATM knockout cells with the addition of chemotherapy.</p>Conclusions:<p><i>ATM</i> mutations define a distinct subset of NSCLC associated with <i>KRAS</i> mutations, increased TMB, decreased <i>TP53</i> and <i>EGFR</i> co-occurrence, and potential increased sensitivity to ICIs in the context of DNA-damaging chemotherapy.</p></div>