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Genome-wide CRISPR-Cas9 screening identifies CLK1 inhibition as a strategy to restore PARP inhibitor sensitivity via

Liu Chaohua1,2,3, Xu Fei2, Wu Yutuan4

  • 1Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

Protein & Cell
|November 5, 2025
PubMed

Insights

Targeting CLK1 with inhibitors can resensitize ovarian cancer to PARP inhibitors (PARPi). This combination therapy enhances DNA damage and apoptosis, offering a new strategy for PARPi-resistant disease.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Epithelial ovarian cancer (EOC) is an aggressive malignancy with limited treatment options.
  • Poly(ADP-ribose) polymerase inhibitors (PARPi) are effective maintenance therapies, particularly for BRCA-mutant patients, but resistance is a significant clinical hurdle.

Purpose of the Study:

  • To identify genes that influence PARPi sensitivity in ovarian cancer using whole-genome CRISPR-Cas9 screening.
  • To investigate the potential of targeting CLK1 in combination with PARPi as a therapeutic strategy for EOC.

Main Methods:

  • Whole-genome CRISPR-Cas9 genetic screening to identify genes affecting PARPi sensitivity.
  • In vitro and in vivo experiments validating the efficacy of combining a PARPi (Olaparib) with a CLK1 inhibitor (TG003).
  • Mechanistic studies to elucidate the molecular pathways involved.

Main Results:

  • CLK1 knockdown was found to be synthetically lethal with PARPi in ovarian cancer.
  • The combination of Olaparib and TG003 demonstrated significant anti-proliferative effects in vitro and in vivo.
  • CLK1 inhibition led to downregulation of the ERCC1-202 isoform, increasing DNA damage and apoptosis.

Conclusions:

  • Targeting CLK1 represents a novel mechanism to overcome PARPi resistance in ovarian cancer.
  • The combination of CLK1 inhibitors and PARPi shows promise as a new therapeutic approach for patients with PARPi-resistant EOC.
Keywords:
CLK1CRISPR-Cas9 screenOvarian cancerPARP inhibitor

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