Oncotarget

Research Papers:

CDK4/6 inhibition as maintenance and combination therapy for high grade serous ovarian cancer

Mangala Iyengar, Patrick O’Hayer, Alex Cole, Tara Sebastian, Kun Yang, Lan Coffman and Ronald J. Buckanovich _

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Oncotarget. 2018; 9:15658-15672. https://doi.org/10.18632/oncotarget.24585

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Abstract

Mangala Iyengar1,2,*, Patrick O’Hayer1,2,*, Alex Cole4, Tara Sebastian3, Kun Yang4, Lan Coffman4,# and Ronald J. Buckanovich4,5,#

1University of Michigan, Department of Cellular and Molecular Biology, Ann Arbor, MI 48109, USA

2University of Michigan, Medical Scientist Training Program, Ann Arbor, MI 48109, USA

3University of Michigan, School of Literature, Science and the Arts, Ann Arbor, MI 48109, USA

4University of Michigan, Division of Hematology and Oncology, Department of Internal Medicine, Ann Arbor, MI 48109, USA

5Magee Women’s Research Institute, University of Pittsburgh, Department of Internal Medicine, Pittsburgh, PA 15213, USA

*Co-first authors

#Co-senior authors

Correspondence to:

Ronald J. Buckanovich, email: ronaldbu@med.umich.edu

Keywords: ovarian cancer; Ribociclib; CDK 4/6 inhibitor; chemotherapy resistance; cell cycle

Abbreviations: LEE-011: Ribociclib; CDK: Cyclin Dependent Kinase; HGSOC: high grade serous ovarian cancer; TCGA: The Cancer Genome Atlas

Received: February 20, 2018     Accepted: February 21, 2018     Epub: February 26, 2018     Published: March 20, 2018

ABSTRACT

High grade serous ovarian cancer (HGSOC) is a disease with a high relapse rate and poor overall survival despite good initial responses to platinum-based therapy. Cell cycle inhibition with targeted CDK4/6 inhibitors is a new therapeutic approach showing promise as a maintenance therapy in cancer. As multiple genes in the CDK4/6 pathway are commonly mutated or dysregulated in ovarian cancer, we evaluated the efficacy of the CDK4/6 inhibitor Ribociclib alone, in combination with chemotherapy, and as maintenance therapy in several models of HGSOC. Ribociclib restricted cellular proliferation in multiple ovarian cancer cell lines. Restricted proliferation was associated with a pseudo-senescent cellular phenotype; Ribociclib-treated cells expressed markers of senescence, but could rapidly re-enter the cell cycle with discontinuation of therapy. Surprisingly, concurrent Ribociclib and cisplatin therapy followed by Ribociclib maintenance was synergistic. Evaluation of the cell cycle suggested that Ribociclib may also act at the G2/M check point via dephosphorylation of ATR and CHK1. Consistent with this mechanism, Ribociclib demonstrated clear activity in both platinum-resistant and platinum-sensitive tumor models in vivo. This work supports clinical trials using Ribociclib in combination with cisplatin and as a maintenance therapy in ovarian cancer.


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