2. Academic Validation
  3. The CHK1 Inhibitor Prexasertib Exhibits Monotherapy Activity in High-Grade Serous Ovarian Cancer Models and Sensitizes to PARP Inhibition

The CHK1 Inhibitor Prexasertib Exhibits Monotherapy Activity in High-Grade Serous Ovarian Cancer Models and Sensitizes to PARP Inhibition

  • Clin Cancer Res. 2019 Oct 15;25(20):6127-6140. doi: 10.1158/1078-0432.CCR-19-0448.
Kalindi Parmar 1 2,  Bose S Kochupurakkal 1 2,  Jean-Bernard Lazaro 1 2,  Zhigang C Wang 3,  Sangeetha Palakurthi 4,  Paul T Kirschmeier 4,  Chunyu Yang 1 2,  Larissa A Sambel 1 2,  Anniina Färkkilä 1 2,  Elizaveta Reznichenko 1 2,  Hunter D Reavis 1 2,  Connor E Dunn 1 2,  Lee Zou 5,  Khanh T Do 6 7,  Panagiotis A Konstantinopoulos 6 7,  Ursula A Matulonis 6 7,  Joyce F Liu 6 7,  Alan D D'Andrea 8 2,  Geoffrey I Shapiro 8 6 7
Affiliations

Affiliations

  • 1 Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 2 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 4 Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 5 Department of Pathology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 7 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • 8 Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts. geoffrey_shapiro@dfci.harvard.edu alan_dandrea@dfci.harvard.edu.
PMID: 31409614 DOI: 10.1158/1078-0432.CCR-19-0448
Abstract

Purpose: PARP inhibitors are approved for the treatment of high-grade serous ovarian cancers (HGSOC). Therapeutic resistance, resulting from restoration of homologous recombination (HR) repair or replication fork stabilization, is a pressing clinical problem. We assessed the activity of prexasertib, a checkpoint kinase 1 (Chk1) inhibitor known to cause replication catastrophe, as monotherapy and in combination with the PARP Inhibitor olaparib in preclinical models of HGSOC, including those with acquired PARP Inhibitor resistance.

Experimental design: Prexasertib was tested as a single agent or in combination with olaparib in 14 clinically annotated and molecularly characterized luciferized HGSOC patient-derived xenograft (PDX) models and in a panel of ovarian Cancer cell lines. The ability of prexasertib to impair HR repair and replication fork stability was also assessed.

Results: Prexasertib monotherapy demonstrated antitumor activity across the 14 PDX models. Thirteen models were resistant to olaparib monotherapy, including 4 carrying BRCA1 mutation. The combination of olaparib with prexasertib was synergistic and produced significant tumor growth inhibition in an olaparib-resistant model and further augmented the degree and durability of response in the olaparib-sensitive model. HGSOC cell lines, including those with acquired PARP Inhibitor resistance, were also sensitive to prexasertib, associated with induction of DNA damage and replication stress. Prexasertib also sensitized these cell lines to PARP inhibition and compromised both HR repair and replication fork stability.

Conclusions: Prexasertib exhibits monotherapy activity in PARP inhibitor-resistant HGSOC PDX and cell line models, reverses restored HR and replication fork stability, and synergizes with PARP inhibition.

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