BRCA Status Does Not Predict Synergism of a Carboplatin and Olaparib Combination in High-Grade Serous Ovarian Cancer Cell Lines

Molecular Pharmaceutics
Yen-Ting ShenMicheline Piquette-Miller

Abstract

Over 50% of epithelial ovarian cancers express the BRCAness profile that leads to a dysfunctional homologous recombination repair system. The combination of a dysfunctional homologous recombination repair system and a poly(ADP-ribose) polymerase (PARP) inhibitor results in a synthetic lethal phenotype. The PARP inhibitor olaparib, approved as a monotherapy for patients with a germline BRCA mutation, has shown promising results in preclinical studies when combined with DNA damaging agents, such as carboplatin. However, dose-limiting toxicities have hindered the use of a combination therapy with olaparib in the clinical setting. By concurrent administration of carboplatin and olaparib at various molar ratios of drugs, the aim of this study was to explore the optimal dosing ratio of carboplatin-olaparib combinations in a comprehensive panel of eight BRCA-proficient and -deficient high-grade serous ovarian cancer (HGSOC) cell lines. Overall, synergy was observed in the BRCA1/2-mutated or defective cell lines when olaparib was combined at lower molar ratios of olaparib to carboplatin. Immunostaining of γH2AX foci revealed increased DNA damage as a result of this synergistic drug combination in the UWB1.289 paired cell lines. In vitr...Continue Reading

References

Jan 1, 1988·Cancer Chemotherapy and Pharmacology·R C GaverF M Muggia
Jul 7, 2000·Seminars in Surgical Oncology·C H Holschneider, J S Berek
Feb 12, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·YanPing HuMarcel Bally
Jun 24, 2006·Molecular Cell·Bing XiaDavid M Livingston
Oct 21, 2006·Biochemical Society Transactions·S J Boulton
Nov 25, 2006·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Murray S WebbMarcel B Bally
May 3, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Cherrie K DonawhoDavid J Frost
Feb 21, 2008·Nature Reviews. Molecular Cell Biology·Dana Branzei, Marco Foiani
Oct 29, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·David S P TanMartin E Gore
Oct 31, 2008·Proceedings of the National Academy of Sciences of the United States of America·Sven RottenbergJos Jonkers
Jun 26, 2009·Human Pathology·C Blake Gilks, Jaime Prat
Jun 26, 2009·The New England Journal of Medicine·Peter C FongJohann S de Bono
Jun 17, 2010·Cancer Research·Ponnari GottipatiThomas Helleday
Sep 28, 2010·Nature Structural & Molecular Biology·Rémi BuissonJean-Yves Masson
Oct 15, 2010·Annals of Oncology : Official Journal of the European Society for Medical Oncology·M A Bookman
Jan 29, 2011·Cancer Control : Journal of the Moffitt Cancer Center·Robert M Wenham
Jan 29, 2011·Cancer Control : Journal of the Moffitt Cancer Center·Janiel Marie Cragun
May 17, 2011·Cancer Research·Euan A StronachHani Gabra
Jul 2, 2011·Nature·UNKNOWN Cancer Genome Atlas Research Network
Mar 1, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Arun RajanGiuseppe Giaccone
Apr 10, 2012·Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging·Meg PerumalEric O Aboagye
Jun 8, 2012·The Oncologist·Georgios Rigakos, Evangelia Razis
Jun 20, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Kathryn AlsopGillian Mitchell
Jul 14, 2012·Expert Opinion on Investigational Drugs·Claudia MarchettiPierluigi Benedetti Panici
Jan 22, 2013·CA: a Cancer Journal for Clinicians·Rebecca SiegelAhmedin Jemal
Jul 11, 2013·Nature Communications·Silvia DomckeNikolaus Schultz
Mar 1, 2014·Frontiers in Oncology·Melissa Burgess, Shannon Puhalla
May 16, 2014·Annals of Oncology : Official Journal of the European Society for Medical Oncology·J BalmañaJ E Garber
Jul 6, 2014·Expert Review of Clinical Pharmacology·Ramez N Eskander, Krishnansu S Tewari
Nov 5, 2014·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Bella KaufmanSusan M Domchek

❮ Previous
Next ❯

Related Concepts

Related Feeds

Breast Cancer: BRCA1 & BRCA2

Mutations involving BRCA1, found on chromosome 17, and BRCA2, found on chromosome 13, increase the risk for specific cancers, such as breast cancer. Discover the last research on breast cancer BRCA1 and BRCA2 here.

Related Papers

Annals of Oncology : Official Journal of the European Society for Medical Oncology
C Sessa
Pharmacogenomics and Personalized Medicine
Kristin Bixel, John L Hays
Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Peter C FongStan B Kaye
Bulletin du cancer
Aurélie Auguste, Alexandra Leary
© 2022 Meta ULC. All rights reserved