TY - JOUR
T1 - ATM Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC
AU - Vokes, Natalie I.
AU - Cobo, Ana Galan
AU - Fernandez-Chas, Margarita
AU - Molkentine, David
AU - Treviño, Santiago
AU - Druker, Vitaly
AU - Qian, Yu
AU - Patel, Sonia
AU - Schmidt, Stephanie
AU - Hong, Lingzhi
AU - Lewis, Jeff
AU - Rinsurongkawong, Waree
AU - Rinsurongkawong, Vadeerat
AU - Lee, J. Jack
AU - Negrao, Marcelo V.
AU - Gibbons, Don L.
AU - Vaporciyan, Ara
AU - Le, Xiuning
AU - Wu, Jia
AU - Zhang, Jianjun
AU - Rigney, Una
AU - Iyer, Sonia
AU - Dean, Emma
AU - Heymach, John V.
N1 - Publisher Copyright:
©2023 The Authors;
PY - 2023
Y1 - 2023
N2 - 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 comutation 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.
AB - 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 comutation 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.
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U2 - 10.1158/1078-0432.CCR-23-1122
DO - 10.1158/1078-0432.CCR-23-1122
M3 - Article
C2 - 37733794
AN - SCOPUS:85178649497
SN - 1078-0432
VL - 29
SP - 4958
EP - 4972
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -