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

• DOI: 10.1158/1078-0432.c.6960649.v1
• Publication Date: 2023-12-01T08:48:36Z
• Authors: Natalie I. Vokes; Ana Galan Cobo; Margarita Fernand...; David Molkentine; Santiago Treviño; Vitaly Druker; Yu Qian; Sonia Patel; Stephanie Schmidt; Lingzhi Hong; Jeff Lewis; Waree Rinsurongka...; Vadeerat Rinsuron...; J. Jack Lee; Marcelo V. Negrao; Don L. Gibbons; Ara Vaporciyan; Xiuning Le; Jia Wu; Jianjun Zhang; Una Rigney; Sonia Iyer; Emma Dean; John V. Heymach

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