Targeting CDK4 and CDK6 kinases in breast cancer development

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Project Summary/Abstract This translational proposal focuses on the use of inhibitors of cyclin-dependent kinases CDK4 and CDK6 for breast cancer treatment. CDK4 and CDK6 are components of the core cell cycle machinery that are activated upon interaction with their regulatory subunits, the D-type cyclins (cyclins D1, D2 and D3). Inhibitors of CDK4/6 palbociclib, ribociclib and abemaciclib received ‘Breakthrough Therapy’ designation status from the FDA and have been approved for treatment of estrogen receptor-positive breast cancers. In addition, these compounds are now in clinical trials for several other cancer types. A large number of studies demonstrated that treatment of human cancer cells with CDK4/6 inhibitors blocks tumor cell proliferation, and in some cases causes tumor cell senescence. Working together with Dr. Polyak, we observed that tumor cells expressing high levels of cyclin D3-CDK6 complexes undergo cell death upon CDK4/6 inhibition. We found that cyclin D3- CDK6, but not several other types of cyclin D-CDK4/6 complexes analyzed by us (such as cyclin D1-CDK4), plays a rate-limiting role in regulating tumor cell metabolism, and protects tumor cells against elevated levels of reactive oxygen species. In an independent study, we found that in mouse and human tumor cells, cyclin D- CDK4 kinase regulates the levels of an immune checkpoint protein, programmed death-ligand 1 (PD-L1). Using mouse cancer models and in vitro cultured cells, we found that treatment with CDK4/6 inhibitors results in upregulation of PD-L1 protein levels in tumor cells. We also found that combined administration of CDK4/6 inhibitors with antibodies that target the interaction between programmed cell death protein 1 (PD-1) and its ligand PD-L1 increased the efficacy of immune checkpoint therapy. In the studies proposed here, we will extend these observations to breast cancers. In Aim 1, we will work with Drs. Polyak and Brown to test our hypothesis that measuring cyclin D3 and CDK6 levels in human breast cancers may allow one to identify breast cancer cases that are particularly sensitive to CDK4/6 inhibitor treatment, as cyclin D3/CDK6-high tumors might undergo tumor cell death and tumor regression upon CDK4/6 inhibition. We will also explore ways to trigger apoptosis of breast cancers expressing predominantly cyclin D1 and CDK4. We will address these issues using xenografts of human breast cancer cell lines and patient-derived breast cancer xenografts. We will also work with Drs. Polyak and Brown to address the intra- and inter-tumoral heterogeneity of breast cancers, which may influence the outcomes. In Aim 2, we test our hypothesis that CDK4/6 inhibitor treatment would increase the efficacy of immune checkpoint therapy for breast cancers and result in tumor regression and improved survival rates in mouse breast cancer models. We will study this using mice bearing breast cancer allografts as well as autochthonous triple-negative breast tumors. The expected overall impact of this proposal is that it will provide means to identify breast cancer cases that are particularly sensitive to anti- CDK4/6 therapy, and establish novel, highly effective combinatorial treatments involving CDK4/6 inhibitors.