Synergistic effect of eribulin and CDK inhibition for the treatment of triple negative breast cancer
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Shreyas S. Rao1, Jenna Stoehr2, Danijela Dokic3, Lei Wan4, Joseph T. Decker5, Kristine Konopka6, Alexandra L. Thomas7, Jia Wu8, Virginia G. Kaklamani9, Lonnie D. Shea3,5 and Jacqueline S. Jeruss3,4,5,6
1Department of Chemical and Biological Engineering, University of Alabama, Tuscaloosa, AL, USA
2Weinberg College of Arts and Sciences, Northwestern University, Evanston, IL, USA
3Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL, USA
4Department of Surgery, University of Michigan, Ann Arbor, MI, USA
5Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
6Department of Pathology, University of Michigan, Ann Arbor, MI, USA
7Driskill Graduate Program, Northwestern University, Chicago, IL, USA
8Department of Chemical and Biological Engineering, McCormick School of Engineering and Applied Science, Northwestern University, Evanston, IL, USA
9Breast Oncology Program, CTRC, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Jacqueline S. Jeruss, email: firstname.lastname@example.org
Keywords: CDK2, eribulin, TGFβ, Smad3, triple negative breast cancer
Received: March 31, 2017 Accepted: July 12, 2017 Published: August 10, 2017
Activation of CDK2 in triple negative breast cancer (TNBC) can contribute to non-canonical phosphorylation of a TGFβ signaling component, Smad3, promoting cell proliferation and migration. Inhibition of CDK2 was shown to decrease breast cancer oncogenesis. Eribulin chemotherapy was used effectively in the treatment of TNBC. To this end, we tested therapeutic efficacy of a novel CDK2/9 inhibitor, CYC065, eribulin, and the combination of CYC065 and eribulin in 3 different TNBC cell lines, and an in vivo xenograft model. Specifically, we characterized cell proliferation, apoptosis, migration, cell cycle associated protein expression, treatment-related transcription factor activity, and tumor growth in TNBC. Treatment with CYC065 and eribulin in combination had a superior effect on decreasing cell proliferation, inducing apoptosis, and inhibiting migration in TNBC cell lines in vitro. Combination therapy inhibited non-canonical Smad3 phosphorylation at the T179 site in the protein linker region, and resulted in increased p15 and decreased c-myc expression. In a transcription factor array, combination treatment significantly increased activity of AP1 and decreased activity of factors including NFκB, SP1, E2F, and SMAD3. In an in vivo xenograft model of TNBC, individual and combination treatments resulted in a decrease in both tumor volume and mitotic indices. Taken together, these studies highlight the potential of this novel drug combination, CYC065 and eribulin, to suppress the growth of TNBC cells in vitro and in vivo, warranting further clinical investigation.
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