Abstract
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.
Highlights
15% of newly diagnosed invasive breast cancer cases lack estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression [1]
We showed that treatment with CYC065 and eribulin synergistically reduced triple negative breast cancer (TNBC) cell viability, tumor colony size, and cell migration, and induced apoptosis in vitro
We showed that treatment was associated with decreased non-canonical Smad3 phosphorylation and mitogenic c-myc expression, as well as increased expression of cell regulatory cdki p15 and G1 cell cycle distribution
Summary
15% of newly diagnosed invasive breast cancer cases lack estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression [1]. Despite the aggressive disease biology and poor outcomes associated with TNBC, currently there are no targeted treatment regimens available for patients with this disease subtype. Treatment of TNBC cells with CYC065, a pharmaceutical grade CDK2/9 inhibitor, blocked the cis-trans isomerase, Pin, and Smad interaction, resulting in decreased cell migration/invasion and impedance of epithelial-mesenchymal transition [11]. These results indicate that CDK inhibitor therapy is a candidate strategy for patients with TNBC
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