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Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Ataxia telangiectasia-mutated (ATM) kinase is a central regulator of the DNA damage response (DDR) signaling pathway, and its function is critical for the maintenance of genomic stability in cells that coordinate a network of cellular processes, including DNA replication, DNA repair, and cell cycle progression. ATM is frequently mutated in human cancers, and approximately 3% of lung cancers have biallelic mutations in ATM, i.e., including 3.5% of lung adenocarcinomas (LUAD) and 1.4% of lung squamous cell carcinomas (LUSC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated the potential of targeting the DDR pathway in lung cancer as a potential therapeutic approach. In this context, we examined whether ATM loss is synthetically lethal with niraparib monotherapy. This exploration involved the use of <jats:italic>hATM<\/jats:italic> knockout (KO) isogenic cell lines containing <jats:italic>hATM<\/jats:italic> homozygous (-\/-) and heterozygous (+\/-) generated via CRISPR\/Cas9 gene knockout technology in DLD-1, a human colorectal adenocarcinoma cell line. Subsequently, we extended our investigation to non-small cell lung cancer (NSCLC) patient derived xenograft (PDX) models for further validation of poly ADP-ribose polymerase inhibitor (PARPi) synthetic lethality in ATM mutant NSCLC models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, we demonstared that biallelic <jats:italic>hATM<\/jats:italic> deletion (-\/-) in DLD-1 impairs homologous recombination (HR) repair function and sensitizes cells to the PARPi, niraparib. Niraparib also caused significant tumor regression in one-third of the NSCLC PDX models harboring deleterious biallelic ATM mutations. Loss of <jats:italic>hATM<\/jats:italic> (\u2212\/\u2212) was concomitantly associated with low BRCA1 and BRCA2 protein expression in both the <jats:italic>hATM<\/jats:italic> (\u2212\/\u2212) DLD-1 cell line and PARPi-sensitive ATM mutant NSCLC PDX models, suggesting a downstream effect on the impairment of HR-mediated DNA checkpoint signaling. Further analysis revealed that loss of ATM led to inhibition of phosphorylation of MRN (Mre11-Rad50-NBS1) complex proteins, which are required for ATM-mediated downstream phosphorylation of p53, BRCA1, and CHK2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Taken together, our findings highlight that the synthetic lethality of niraparib in ATM-deficient tumors can be regulated through a subsequent effect on the modulation of BRCA1\/2 expression and its effect on HR function.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2024.1380633","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T12:50:49Z","timestamp":1715691049000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["PARP inhibitor synthetic lethality in ATM biallelic mutant cancer cell lines is associated with BRCA1\/2 and RAD51 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