Fischer Thomas, Hartmann Oliver, Reissland Michaela, Prieto-Garcia Cristian, Klann Kevin, Pahor Nikolett, Schülein-Völk Christina, Baluapuri Apoorva, Polat Bülent, Abazari Arya, Gerhard-Hartmann Elena, Kopp Hans-Georg, Essmann Frank, Rosenfeldt Mathias, Münch Christian, Flentje Michael, Diefenbacher Markus E
Department of Radiation Oncology, University Hospital Würzburg, Würzburg, Germany.
Department of Biochemistry and Molecular Biology, Protein Stability and Cancer Group, University of Würzburg, Würzburg, Germany.
Cell Biosci. 2022 Apr 27;12(1):50. doi: 10.1186/s13578-022-00778-7.
Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy.
We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model.
PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.
尽管非小细胞肺癌患者的治疗取得了进展，但某些基因改变的携带者仍易于治疗失败。其中一个经常发生突变的因素是肿瘤抑制因子PTEN。这些肿瘤被认为对放疗、化疗和免疫疗法更具抗性。
我们证明，PTEN的缺失导致直接调节治疗抗性的转录程序表达改变，从而导致辐射抗性的建立。虽然PTEN缺陷的肿瘤细胞对辐射抗性不依赖于DNA-PK，在辐射期间也不激活ATR，但它们对DNA损伤激酶ATM有显著依赖性。通过无毒剂量的KU-60019和AZD1390对ATM进行药理学抑制，在PTEN缺陷的人和小鼠非小细胞肺癌细胞以及多细胞器官型体外肿瘤模型中，恢复了辐射敏感性，甚至与辐射产生协同作用。
PTEN肿瘤依赖ATM来检测和修复辐射诱导的DNA损伤。这创造了一个可利用的瓶颈。至少在细胞内和体外，我们表明低浓度的ATM抑制剂能够与辐射协同作用，以治疗基因明确的辐射抗性肺癌模型中的PTEN缺陷肿瘤。
