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Resistance to the CHK1 inhibitor prexasertib involves functionally distinct CHK1 activities in BRCA wild-type ovarian

Jayakumar Nair1, Tzu-Ting Huang2, Junko Murai3

  • 1Women's Malignancies Branch, National Institutes of Health, Bethesda, 20892, MD, USA. jayakumar.nair@nih.gov.

Oncogene
|July 11, 2020
PubMed

Insights

High-grade serous ovarian cancer (HGSOC) resistance to CHK1 inhibitors involves a G2 cell cycle delay. Combination therapy with DNA damaging agents may overcome this resistance in BRCA wild-type HGSOC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • High-grade serous ovarian cancer (HGSOC) presents limited treatment options, driving research into novel therapeutic strategies.
  • Targeting cell cycle checkpoints, such as ATR and CHK1, is a promising avenue for HGSOC treatment.
  • Prexasertib, a CHK1 inhibitor, has shown clinical activity as monotherapy in BRCA wild-type (BRCAwt) HGSOC.

Purpose of the Study:

  • To investigate mechanisms of resistance to CHK1 inhibitor (CHK1i) prexasertib monotherapy in BRCAwt HGSOC.
  • To elucidate the role of CHK1 in regulating cell cycle progression and DNA repair in the context of resistance.
  • To identify potential combination strategies to overcome CHK1i resistance.

Main Methods:

  • Analysis of patient biopsies and cell line models from HGSOC patients treated with prexasertib.
  • Assessment of cell cycle progression, specifically G2 delay and mitotic catastrophe.
  • Evaluation of homologous recombination (HR) repair pathways, including RAD51 activity.
  • Testing the efficacy of CHK1i in combination with DNA damaging agents (gemcitabine, hydroxyurea).

Main Results:

  • BRCAwt HGSOC develops resistance to prexasertib via a prolonged G2 delay, mediated by reduced CDK1/CyclinB1 activity, which prevents mitotic catastrophe.
  • CHK1's regulation of RAD51-mediated homologous recombination (HR) repair remains functional in CHK1i-resistant cells.
  • CHK1 inhibition sensitizes resistant cells to DNA damaging agents by inhibiting HR.

Conclusions:

  • Distinct functional activities of CHK1 in cell cycle progression and DNA repair contribute to HGSOC resistance mechanisms.
  • Combination therapy involving CHK1 inhibitors and DNA damaging agents represents a viable strategy to overcome prexasertib resistance in BRCAwt HGSOC.

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