ATM

  • Ataxia-telangiectasia mutated (ATM)
  • Gene location: chromosome 11 (11q22-11q23)

Biology

  • The ataxia-telangiectasia mutated (ATM) gene that is located on chromosome 11q22-q23 encodes ATM, a large serine/threonine kinase is a central regulator of the DNA damage response (DDR).1
  • Structurally, ATM belongs to the PI3K-related kinase (PIKK) family, sharing conserved domains involved in DNA repair signaling.1
  • Under normal conditions, ATM exists as an inactive dimer or multimer. In response to DNA double-strand breaks, it becomes activated through autophosphorylation at Ser1981, leading to dissociation into active monomers.1
  • These monomers then phosphorylate key downstream targets involved in the DNA damage response (including TP53, CHK2, H2AX, and BRCA1), thereby coordinating cell cycle arrest, DNA repair, or apoptosis.1
  • Loss or mutation of ATM disrupts these checkpoint and repair pathways, leading to genomic instability, accumulation of mutations, and malignant transformation.1,2
  • In preclinical mouse models, combined loss of ATM and activation of oncogenic KRAS drives the formation of aggressive pancreatic ductal adenocarcinoma (PDAC), emphasizing ATM’s role as a tumor suppressor.2

Etiology & Epidemiology

  • Approximately 1% to 3% of patients with pancreatic cancer harbor germline ATM mutations; individuals with this mutation have a 6.5-fold increased lifetime risk of developing the disease compared to noncarriers.3
  • Somatic alterations (mutations or loss of expression) of ATM occur in 5% to 18% of PDAC tumors and are associated with deficient DNA repair mechanisms.1
  • These mutations are more frequently observed in familial pancreatic cancer, suggesting a role in hereditary predisposition.3,4

Testing

When to Test:

  • ATM testing is recommended for all patients diagnosed with PDAC, regardless of age or family history.5
  • Additional indications include:
    • Personal or family history suggestive of hereditary cancer syndromes (eg, familial pancreatic cancer)5
    • Early-onset PDAC (age, typically < 50 years)5
    • Eligibility for clinical trials involving DDR-targeted therapies (eg, ATR or PARP inhibitors).5

Available Testing Methods:

  • Germline testing involves multigene panel sequencing on blood or saliva, typically ordered through commercial or institutional genetic testing services.4
  • Somatic testing is conducted via next-generation sequencing (NGS) on tumor tissue to detect acquired (noninherited) mutations.5
  • Immunohistochemistry (IHC) for ATM protein expression is not part of standard clinical practice but may be used in research settings to assess ATM loss or functionality.1

Guideline Recommendations:

  • The NCCN Guidelines (version 2.2025) recommend:
    • Germline testing, including of ATM, for all patients with PDAC regardless of clinical or family history.5
    • Somatic NGS testing to guide treatment with platinum agents, PARP inhibitors, or investigational DDR-targeted therapies.5
    • IHC is not routinely recommended but may be incorporated into future clinical trials or exploratory end points.1

Targeted Therapy

FDA-Approved Agents:

  • There are currently no FDA-approved therapies that specifically target ATM mutations in PDAC.5

Investigational Agents:

  • Platinum agents (eg, oxaliplatin)1,6
    • Platinum chemotherapy agents have enhanced activity in ATM-deficient tumors; this is likely due to their mechanism of inducing DNA crosslinks and double-strand breaks, which ATM-deficient cells cannot repair effectively.
  • PARP inhibitors (eg, olaparib, talazoparib)1,7
    • PARP inhibitors are being studied in ATM-mutant PDAC, although their efficacy is less well established compared to BRCA-mutant tumors.
    • Early data suggest limited single-agent activity in ATM-deficient cancers, but combination strategies (eg, with ATR inhibitors or checkpoint blockade) are being evaluated.
  • ATR inhibitors
    • Ceralasertib (AZD6738)1,8
      • Exploits synthetic lethality in the setting of ATM loss; being tested alone and in combination with chemotherapy or immunotherapy
      • Mechanism of action:
        • Ceralasertib is a selective oral ATR kinase inhibitor that disrupts the DNA damage response by blocking replication stress checkpoints.
        • It is particularly effective in tumors with ATM deficiency that rely more on ATR.
        • By inhibiting ATR, ceralasertib causes accumulation of DNA damage and replication fork collapse, leading to tumor cell death via synthetic lethality.
      • Investigational studies:
        • Phase 2 study9
          • ClinicalTrials.gov: NCT03682289
          • Study design: Phase 2 trial evaluating ceralasertib (AZD6738) alone and in combination with olaparib or durvalumab in patients with selected solid tumor malignancies, including advanced PDAC

References

  1. Armstrong SA, Schultz CW, Azimi-Sadjadi A, Brody JR, Pishvaian MJ. ATM dysfunction in pancreatic adenocarcinoma and associated therapeutic implications. Mol Cancer Ther. 2019;18(11):1899-1908. doi:10.1158/1535-7163.MCT-19-0208
  2. Russell R, Perkhofer L, Liebau S, et al. Loss of ATM accelerates pancreatic cancer formation. Nat Commun. 2015;6:7677. doi:10.1038/ncomms8677
  3. Roberts NJ, Jaio Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. CancerDiscov. 2012;2(1):41-46. doi:10.1158/2159-8290.CD-11-0194
  4. Lowery MA, Wong W, Jordan EJ, et al. Prospective evaluation of germline alterations in exocrine pancreatic neoplasms. J Natl Cancer Inst. 2018;110(10):1067-1074. doi:10.1093/jnci/djy024
  5. NCCN. Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, version 2.2025. Accessed July 25, 2025. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
  6. Choi M, Kipps T, Kurzrock R. ATM mutations in cancer: therapeutic implications. Mol Cancer Ther. 2016;15(8):1781-1791. doi:10.1158/1535-7163.MCT-15-0945
  7. Hannan Z, Yu S, Domchek S, Mamtani R, Reiss KA. Clinical Characteristics of Patients With Pancreatic Cancer and Pathogenic ATM Alterations. JNCI CancerSpectr. 2021 Jan 23;5(2):pkaa121. doi: 10.1093/jncics/pkaa121
  8. Yap TA, O'Carrigan B, Penney MS, et al. Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors. J Clin Oncol. 2020;38(27):3195-3204. doi: 10.1200/JCO.19.02404
  9. Ceralasertib (AZD6738) alone and in combination with olaparib or durvalumab in patients with solid tumors. ClinicalTrials.gov. Updated June 6, 2025. Accessed June 30, 2025. https://clinicaltrials.gov/study/NCT03682289