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Targeting DNA-PK overcomes acquired resistance to third-generation EGFR-TKI osimertinib in non-small-cell lung cancer

Xing-Mei Liang1,2, Qiong Qin1,2, Bo-Ning Liu1

  • 1Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.

Acta Pharmacologica Sinica
|January 8, 2021
PubMed

Insights

Osimertinib resistance in non-small cell lung cancer (NSCLC) may stem from impaired DNA repair. Targeting DNA-PK kinase with inhibitors can re-sensitize resistant cells to osimertinib, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) like osimertinib show promise for EGFR-mutated non-small cell lung cancer (NSCLC).
  • Acquired resistance to osimertinib is a significant clinical challenge, with underlying mechanisms requiring further elucidation.

Purpose of the Study:

  • To investigate the role of DNA damage repair (DDR) in osimertinib resistance in NSCLC.
  • To explore targeting DNA-dependent protein kinase (DNA-PK) as a strategy to overcome osimertinib resistance.

Main Methods:

  • Generation of an osimertinib-acquired resistant NSCLC cell line model.
  • Assessment of DNA damage repair capacity using markers like γH2AX and comet assays.
  • Evaluation of DNA-PK inhibition (pharmacological and genetic) on cell sensitivity to osimertinib.
  • Combination therapy studies with osimertinib and DNA-PK inhibitors (PI-103, NU7441).

Main Results:

  • Osimertinib-resistant cells exhibited compromised DNA damage repair.
  • Inhibition of DNA-PK sensitized resistant cells to osimertinib.
  • Combination of osimertinib with DNA-PK inhibitors synergistically inhibited resistant cell proliferation.
  • Combined treatment led to prolonged DNA damage and cell cycle arrest.

Conclusions:

  • Impaired DNA repair is a key mechanism in acquired osimertinib resistance in NSCLC.
  • Targeting DNA-PK represents a promising therapeutic strategy to overcome osimertinib resistance in NSCLC patients.
Keywords:
DNA damage repairDNA-PKEGFR-TKI resistanceNSCLCosimertinib

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