ATM Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC

Authors

Natalie I Vokes
Ana Galan Cobo
Margarita Fernandez-Chas
David Molkentine
Santiago Treviño
Vitaly Druker
Yu Qian
Sonia Patel
Stephanie Schmidt
Lingzhi Hong
Jeff Lewis
Waree Rinsurongkawong
Vadeerat Rinsurongkawong
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

Publication Date

12-1-2023

Journal

Clinical Cancer Research

Abstract

PURPOSE: Ataxia-telangiectasia mutated (ATM) is the most frequently mutated DNA damage repair gene in non-small cell lung cancer (NSCLC). However, the molecular correlates of ATM mutations and their clinical implications have not been fully elucidated.

EXPERIMENTAL DESIGN: 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 ATM-mutant tumors. We used the CGDB to evaluate ATM-associated outcomes in patients treated with immune checkpoint inhibitors (ICI) with or without chemotherapy, and assessed the effect of ATM loss on STING signaling and chemotherapy sensitivity in preclinical models.

RESULTS: Nonsynonymous mutations in ATM were observed in 11.2% of samples (2,980/26,587) and were significantly associated with mutations in KRAS, but mutually exclusive with EGFR (q < 0.1). KRAS mutational status constrained the ATM co-mutation landscape, with strong mutual exclusivity with TP53 and KEAP1 within KRAS-mutated samples. Those ATM mutations that co-occurred with TP53 were more likely to be missense mutations and associate with high mutational burden, suggestive of non-functional passenger mutations. In the CGDB cohort, dysfunctional ATM mutations associated with improved OS only in patients treated with ICI-chemotherapy, and not ICI alone. In vitro analyses demonstrated enhanced upregulation of STING signaling in ATM knockout cells with the addition of chemotherapy.

CONCLUSIONS: ATM mutations define a distinct subset of NSCLC associated with KRAS mutations, increased TMB, decreased TP53 and EGFR co-occurrence, and potential increased sensitivity to ICIs in the context of DNA-damaging chemotherapy.

Keywords

Humans, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Kelch-Like ECH-Associated Protein 1, Ataxia Telangiectasia, Proto-Oncogene Proteins p21(ras), NF-E2-Related Factor 2, Mutation, ErbB Receptors, Ataxia Telangiectasia Mutated Proteins

Comments

Supplementary Materials

PMID: 37733794