PARP-1 activity (PAR) determines the sensitivity of cervical cancer to olaparib

Anna Bianchi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Salvatore Lopez, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro 88100, Italy.
Gary Altwerger, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Stefania Bellone, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Elena Bonazzoli, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Luca Zammataro, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Aranzazu Manzano, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Paola Manara, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Emanuele Perrone, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Women's and Children's Health, "Agostino Gemelli" Foundation University Hospital, Catholic University, Rome, Italy.
Burak Zeybek, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Chanhee Han, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Gulden Menderes, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Elena Ratner, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Dan-Arin Silasi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Gloria S. Huang, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Masoud Azodi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.Follow
Justin Y. Newberg, Cancer Genomics Research, Foundation Medicine, Cambridge, MA 02141, USA.
Dean C. Pavlick, Cancer Genomics Research, Foundation Medicine, Cambridge, MA 02141, USA.
Julia Elvin, Cancer Genomics Research, Foundation Medicine, Cambridge, MA 02141, USA.
Garrett M. Frampton, Cancer Genomics Research, Foundation Medicine, Cambridge, MA 02141, USA.
Peter E. Schwartz, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
Alessandro D. Santin, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: alessandro.santin@yale.edu.

Document Type

Article

Publication Title

Gynecologic oncology

Abstract

OBJECTIVES: Cervical cancer (CC) remains a major health problem worldwide. Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi) have emerged as a promising class of chemotherapeutics in ovarian cancer. We explored the preclinical in vitro and in vivo activity of olaparib against multiple primary whole exome sequenced (WES) CC cells lines and xenografts. METHODS: Olaparib cell-cycle, apoptosis, homologous-recombination-deficiency (HRD), PARP trapping and cytotoxicity activity was evaluated against 9 primary CC cell lines in vitro. PARP and PAR expression were analyzed by Western blot assays. Finally, olaparib in vivo antitumor activity was tested against CC xenografts. RESULTS: While none of the cell lines demonstrated HRD, three out of 9 (33.3%) primary CC cell lines showed strong PARylation activity and demonstrated high sensitivity to olaparib in vitro treatment (cutoff IC values < 2 μM, p = 0.0012). Olaparib suppressed CC cell growth through cell cycle arrest in the G2/M phase and caused apoptosis (p < 0.0001). Olaparib activity in CC involved both PARP enzyme inhibition and trapping. In vivo, olaparib significantly impaired CC xenografts tumor growth (p = 0.0017) and increased overall animal survival (p = 0.008). CONCLUSIONS: A subset of CC primary cell lines is highly responsive to olaparib treatment in vitro and in vivo. High level of PARylation correlated with olaparib preclinical activity and may represent a useful biomarker for the identification of CC patients benefitting the most from PARPi.

First Page

144

Last Page

150

DOI

10.1016/j.ygyno.2019.08.010

Publication Date

10-1-2019

Identifier

31434613 (pubmed); NIHMS1537725 (mid); PMC6788971 (pmc); 10.1016/j.ygyno.2019.08.010 (doi); S0090-8258(19)31461-1 (pii)

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