Entinostat, a selective HDAC1/2 inhibitor, potentiates the effects of olaparib in homologous recombination proficient ovarian cancer.

Autor: Gupta VG; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA., Hirst J; Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, The University of Kansas Medical Center, Kansas City, KS 66160, USA., Petersen S; Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, The University of Kansas Medical Center, Kansas City, KS 66160, USA., Roby KF; Department of Anatomy and Cell Biology, The University of Kansas Medical Center, Kansas City, KS 66160, USA., Kusch M; Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, The University of Kansas Medical Center, Kansas City, KS 66160, USA., Zhou H; Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, The University of Kansas Medical Center, Kansas City, KS 66160, USA., Clive ML; Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, The University of Kansas Medical Center, Kansas City, KS 66160, USA., Jewell A; Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, The University of Kansas Medical Center, Kansas City, KS 66160, USA., Pathak HB; Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA., Godwin AK; Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA; Univeristy of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS 66160, USA., Wilson AJ; Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN 37235, USA., Crispens MA; Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN 37235, USA., Cybulla E; Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA., Vindigni A; Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA., Fuh KC; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA., Khabele D; Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: khabeled@wustl.edu.
Jazyk: angličtina
Zdroj: Gynecologic oncology [Gynecol Oncol] 2021 Jul; Vol. 162 (1), pp. 163-172. Date of Electronic Publication: 2021 Apr 16.
DOI: 10.1016/j.ygyno.2021.04.015
Abstrakt: Objective: Poly ADP ribose polymerase inhibitors (PARPi) are most effective in BRCA1/2 mutated ovarian tumors. Better treatments are needed for homologous recombination HR-proficient cancer, including CCNE1 amplified subtypes. We have shown that histone deacetylase inhibitors (HDACi) sensitize HR-proficient ovarian cancer to PARPi. In this study, we provide complementary preclinical data for an investigator-initiated phase 1/2 clinical trial of the combination of olaparib and entinostat in recurrent, HR-proficient ovarian cancer.
Methods: We assessed the in vitro effects of the combination of olaparib and entinostat in SKOV-3, OVCAR-3 and primary cells derived from CCNE1 amplified high grade serous ovarian cancer (HGSOC) patients. We then tested the combination in a SKOV-3 xenograft model and in a patient-derived xenograft (PDX) model.
Results: Entinostat potentiates the effect of olaparib in reducing cell viability and clonogenicity of HR-proficient ovarian cancer cells. The combination reduces peritoneal metastases in a SKOV-3 xenograft model and prolongs survival in a CCNE1 amplified HR-proficient PDX model. Entinostat also enhances olaparib-induced DNA damage. Further, entinostat decreases BRCA1, a key HR repair protein, associated with decreased Ki-67, a proliferation marker, and increased cleaved PARP, a marker of apoptosis. Finally, entinostat perturbs replication fork progression, which increases genome instability.
Conclusion: Entinostat inhibits HR repair by reducing BRCA1 expression and stalling replication fork progression, leading to irreparable DNA damage and ultimate cell death. This work provides preclinical support for the clinical trial of the combination of olaparib and entinostat in HR-proficient ovarian cancer and suggests potential benefit even for CCNE1 amplified subtypes.
Competing Interests: Declaration of Competing Interest Dr. Khabele: Grant support from Astra-Zeneca and Deciphera, and speaker's Bureau for Astra Zeneca. Dr. Crispens: Grant support from Astra-Zeneca. Dr. Fuh: Grant support from Merck and is on advisory board of Genentech, Immunogen, GSK, Myriad and Aravive. Dr. Godwin: Co-founder of Sinochips Diagnostics and received support from Biovica and VITRAC Therapeutics, LLC. Remaining authors have no COI or disclosures.
(Copyright © 2021. Published by Elsevier Inc.)
Databáze: MEDLINE
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