ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies with very few therapeutic options to treat advanced or metastatic disease. The utilization of genomic sequencing has identified therapeutically relevant alterations in approximately 25% of PDAC patients, most notably in the DNA damage response and repair (DDR) genes, rendering cancer cells more sensitive to DNA-damaging agents and to DNA damage response inhibitors, such as PARP inhibitors. ATM is one of the most commonly mutated DDR genes, with somatic mutations identified in 2% to 18% of PDACs and germline mutations identified in 1% to 34% of PDACs. ATM plays a complex role as a cell-cycle checkpoint kinase, regulator of a wide array of downstream proteins, and responder to DNA damage for genome stability. The disruption of ATM signaling leads to downstream reliance on ATR and CHK1, among other DNA-repair mechanisms, which may enable exploiting the inhibition of downstream proteins as therapeutic targets in ATM-mutated PDACs. In this review, we detail the function of ATM, review the current data on ATM deficiency in PDAC, examine the therapeutic implications of ATM alterations, and explore the current clinical trials surrounding the ATM pathway.