CDK4/6 inhibition as maintenance and combination therapy for high grade serous ovarian cancer
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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
Ronald J. Buckanovich, email: [email protected]
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
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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