ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications

Abstract

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.

DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives

“…The combinatorial use of ATR inhibitors with conventional chemotherapy or PARP inhibitors in patients with ATM-deficient PDAC seems interesting, as it could assign HRDness to a given cancer. 107 This is currently being assessed in various recruiting trials; for more details see table 6 .…”

Durable Near-Complete Response to Olaparib Plus Temozolomide and Radiation in a Patient With ATM-Mutated Glioblastoma and MSH6-Deficient Lynch Syndrome

“…Inactivating mutations in ATM result in DDR-deficient tumors that are susceptible to synthetic lethality with DNA-damaging agents and PARPi. 42 , 43 In the absence of data, it may be predicted that a tumor both dMMR and DDR deficient is exceptionally unstable and susceptible to synthetic lethality, although the complexity of the roles of MSH6 and ATM in DNA repair and apoptosis make this uncertain.…”

Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

“…PC remains one of the most lethal solid malignancies. The identification of damaging mutations in DDR system genes, including ATM , in 17–25% of this type of cancer and the recent suggestion that PARP inhibitors could have therapeutic potential in cancers with loss or mutation of ATM are opening up the possibility of new therapies, such as platinum and more recently PARP inhibitors, also in ATM -mutated patients with PC [ 83 , 84 , 85 ].…”