The Poly (ADP-ribose) polymerase inhibitor olaparib and pan-ErbB inhibitor neratinib are highly synergistic in HER2 overexpressing epithelial ovarian carcinoma in vitro and in vivo.

Humans Female Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use Carcinoma, Ovarian Epithelial / drug therapy Ribose / therapeutic use Antineoplastic Agents / therapeutic use Phthalazines / therapeutic use Ovarian Neoplasms / pathology Poly (ADP-Ribose) Polymerase-1 / metabolism Poly(ADP-ribose) Polymerases / metabolism Cell Line, Tumor

HER2 Neratinib Olaparib Ovarian cancer PARP inhibitors

Journal

Gynecologic oncology

ISSN: 1095-6859

Titre abrégé: Gynecol Oncol

Pays: United States

ID NLM: 0365304

Informations de publication

Date de publication:
03 2023

Historique:

received: 10 11 2022

revised: 22 12 2022

accepted: 16 01 2023

pmc-release: 01 03 2024

pubmed: 28 1 2023

medline: 15 3 2023

entrez: 27 1 2023

Statut: ppublish

Résumé

Ovarian cancer (OC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical efficacy of the Poly (ADP-ribose) polymerase (PARP) inhibitor (olaparib) and the pan-ErbB inhibitor (neratinib) as single agents and in combination in ovarian cancer cell lines and xenografts with variable HER2 expression. In vitro cell viability with olaparib, neratinib, and their combination was assessed using flow-cytometry based assays against a panel of OC primary cell lines with variable HER2 expression. Immunoblotting experiments were performed to elucidate the mechanism of activity and synergism. The in vivo antitumor activity of the olaparib/neratinib combination versus single agents was tested in HER2 positive xenograft OC models. HER2 + OC cell lines demonstrated higher sensitivity to olaparib and neratinib when compared to HER2 negative tumors (i.e., IC The combination of olaparib and neratinib is synergistic and endowed with remarkable preclinical activity against HER2+ ovarian cancers. This combination may represent a novel therapeutic option for ovarian cancer patients with HER2+, homologous recombination-proficient tumors resistant to chemotherapy.

Identifiants

DOI: 10.1016/j.ygyno.2023.01.015 PMID: 36706643 PMC: PMC10023457

pubmed: 36706643

pii: S0090-8258(23)00015-X

doi: 10.1016/j.ygyno.2023.01.015

pmc: PMC10023457

mid: NIHMS1868705

pii:

doi:

Substances chimiques

Poly(ADP-ribose) Polymerase Inhibitors 0

neratinib JJH94R3PWB

olaparib WOH1JD9AR8

Ribose 681HV46001

Antineoplastic Agents 0

Phthalazines 0

Poly (ADP-Ribose) Polymerase-1 EC 2.4.2.30

Poly(ADP-ribose) Polymerases EC 2.4.2.30

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

172-178

Subventions

Organisme : NCI NIH HHS

ID : U01 CA176067

Pays : United States

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of Competing Interest Dr. Santin declares grants from PUMA, grants from IMMUNOMEDICS, grants from GILEAD, grants from SYNTHON, grants and personal fees from MERCK, grants from BOEHINGER-INGELHEIM, grants from GENENTECH, grants and personal fees from TESARO and grants and personal fees from EISAI and R-PHARM-US. The other authors declare no conflict of interest.

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