PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy

Abstract
Background: Despite progress in treating non-small cell lung cancer (NSCLC), patients with certain genetic mutations continue to face challenges. One such mutation involves the tumor suppressor PTEN, which is frequently altered in these cancers. Tumors with PTEN mutations are often more resistant to radiation, chemotherapy, and immunotherapy.

Results: Our research reveals that the loss of PTEN causes changes in transcriptional programs that directly influence therapy resistance, leading to increased radiation resistance. PTEN-deficient tumor cells do not rely on DNA-PK for resistance to ionizing radiation (IR) nor do they activate ATR in response to IR. Instead, these cells exhibit a significant dependence on the DNA damage kinase ATM. Using low doses of the ATM inhibitors KU-60019 and AZD1390, we found that these inhibitors restored and even enhanced the effectiveness of IR in both PTEN-deficient human and murine NSCLC cells, as well as in an ex vivo multicellular tumor model.

Conclusion: Tumors with PTEN mutations rely heavily on ATM for detecting and repairing radiation-induced DNA damage, creating a potential target for treatment. Our findings demonstrate that low concentrations of ATM inhibitors can effectively synergize with IR to treat PTEN-deficient tumors in well-defined models of radiation-resistant AZD1390 lung cancer.