In:
Clinical Cancer Research, American Association for Cancer Research (AACR), ( 2023-09-21)
Abstract:
Introduction: 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. Methods: Clinicopathologic and genomic data from 26,587 NSCLC patients from MD Anderson, public databases, and a de-identified nationwide (US-based) NSCLC clinico-genomic database (CGDB) were used to assess the co-mutation landscape, protein expression, and mutational processes in ATM-mutant tumors. We utilized the CGDB to evaluate ATM-associated outcomes in patients treated with immune checkpoint inhibitors (ICIs) 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 (2980/26,587) and were significantly associated with mutations in KRAS, but mutually exclusive with EGFR (q & lt;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 knock-out 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.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1078-0432.CCR-23-1122
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9
