Journal
ACTA PHARMACOLOGICA SINICA
Volume 42, Issue 4, Pages 648-654Publisher
NATURE PUBL GROUP
DOI: 10.1038/s41401-020-00577-1
Keywords
NSCLC; EGFR-TKI resistance; osimertinib; DNA damage repair; DNA-PK
Funding
- National Natural Science Foundation of China [81972186, 31301160, 81572268, 81702678]
- Natural Science Foundation of Tianjin [20JCYBJC00360, 16JCYBJC24400, 17JCYBJC25500]
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The study reveals that DNA damage repair capacity is compromised in osimertinib-resistant cells, and inhibiting DNA-PK can increase sensitivity to osimertinib. Combination of osimertinib with DNA-PK inhibitors synergistically suppresses proliferation of resistant cells.
The third-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), represented by osimertinib, has achieved remarkable clinical outcomes in the treatment of non-small-cell lung cancer (NSCLC) with EGFR mutation. However, resistance eventually emerges in most patients and the underlying molecular mechanisms remain to be fully understood. In this study, we generated an osimertinib-acquired resistant lung cancer model from a NSCLC cell line H1975 harboring EGFR L858R and T790M mutations. We found that the capacity of DNA damage repair was compromised in the osimertinib resistant cells, evidenced by increased levels of gamma H2AX and higher intensity of the comet tail after withdrawal from cisplatin. Pharmacological inhibiting the activity or genetic knockdown the expression of DNA-PK, a key kinase in DNA damage response (DDR), sensitized the resistant cells to osimertinib. Combination of osimertinib with the DNA-PK inhibitor, PI-103, or NU7441, synergistically suppressed the proliferation of the resistant cells. Mechanistically, we revealed that DNA-PK inhibitor in combination with osimertinib resulted in prolonged DNA damage and cell cycle arrest. These findings shed new light on the mechanisms of osimertinib resistance in the aspect of DNA repair, and provide a rationale for targeting DNA-PK as a therapeutic strategy to overcome osimertinib-acquired resistance in NSCLC.
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