Pharmaceutical Sciences Seminar
Faculty Candidate

Jen Haizhen Wang, PhD
Department of Cancer Biology, Dana-Farber Cancer Institute
Harvard Medical School

Cyclin D-CDK4/6 Kinase in Cancer Cell Survival and Immune Surveillance

Cyclin D-CDK4/6 are components of the core cell cycle machinery that drives cell proliferation. Inhibitors of CDK4/6 are currently in clinical trials for several cancer types with promising results. We show that cyclin D3-CDK6 plays pro-survival function via phosphorylation and inhibition the catalytic activities of 6-phosphofructokinase (PFKP) and pyruvate kinase M2 (PKM2). Inhibition of cyclin D3-CDK6 in tumor cells activates PFKP and PKM2 to reduce pentose phosphate pathway and serine pathway flows, thereby depleting anti-oxidants NADPH and glutathione to cause tumor cell apoptosis. We propose that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumor subsets that undergo cell death and tumor regression upon CDK4/6-inhibition. On the other hand, we report that cyclin D-CDK4 negatively regulates PD-L1 stability through phosphorylating and stabilizing its upstream E3 ligase adaptor protein SPOP. Inhibition of cyclin D-CDK4 upregulates PD-L1 protein levels in tumor cells to generate immune evasion effect. We also show that combining CDK4/6 inhibitor with PD-1 blockade enhances anti-tumor therapeutic efficacy in mouse models. This study provides the molecular basis for combination therapy of CDK4/6 inhibitor and PD-1/PD-L1 blockade for human cancers.