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

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Ataxia-telangiectasia mutated (ATM) is a key DNA damage repair gene frequently altered in non-small cell lung cancer (NSCLC).
• The molecular landscape and clinical impact of ATM mutations in NSCLC remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular correlates of ATM mutations in NSCLC.
• To investigate the clinical implications of ATM mutations, particularly in response to immune checkpoint inhibitors (ICIs).

Main Methods:

• Analysis of clinicopathologic and genomic data from over 26,000 NSCLC patients.
• Assessment of ATM mutation co-occurrence, protein expression, and mutational processes.
• Evaluation of ATM-associated outcomes in patients treated with ICIs, with or without chemotherapy.
• Preclinical studies on ATM loss, STING signaling, and chemotherapy sensitivity.

Main Results:

• ATM mutations occurred in 11.2% of NSCLC samples, significantly associated with KRAS mutations and mutually exclusive with EGFR mutations.
• ATM mutations showed distinct co-mutation patterns with KRAS, TP53, and KEAP1.
• Dysfunctional ATM mutations were linked to improved overall survival (OS) in patients receiving ICI plus chemotherapy, but not ICI alone.
• In vitro studies showed enhanced STING signaling and chemotherapy sensitivity in ATM-deficient cells.

Conclusions:

• ATM mutations identify a unique NSCLC subtype characterized by KRAS mutations, high tumor mutational burden (TMB), and altered co-mutation profiles.
• ATM-mutant NSCLC may exhibit increased sensitivity to combination therapy with ICIs and DNA-damaging chemotherapy.