D-type cyclins (D1, D2 and D3) together with their associated cyclin-dependent kinases CDK4 and CDK6 are components of the core cell cycle machinery that drives cell proliferation. Inhibitors of CDK4 and CDK6 are currently in clinical trials for patients with several cancer types, with promising results. We demonstrated that cyclin D3-CDK6 phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. This re-directs the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumor cells reduces PPP and serine pathway flows, thereby depleting anti-oxidants NADPH and glutathione. This, in turn, elevates the levels of reactive oxygen species and causes tumor cell apoptosis. The pro-survival function of cyclin D-associated kinase operates in tumors expressing high levels of cyclin D3-CDK6 complexes. 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. Cyclin D3-CDK6, through its ability to link cell cycle and cell metabolism represents a particularly powerful oncogene that affects cancer cells at several levels, and this property can be exploited for anti-cancer therapy.
Targeting immune checkpoints such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1 have been approved for treating multiple types of human cancers with durable clinical benefit. However, many cancer patients fail to respond to anti-PD-1/PD-L1 treatment, and the underling mechanism(s) is not well understood. Recent studies revealed that response to PD-L1 blockade might correlate with PD-L1 expression levels on tumor cells. Hence, it is important to mechanistically understand the pathways controlling PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients. We found that PD-L1 protein abundance is regulated by cyclin D-CDK4, and that inhibition of CDK4/6 in vivo elevates PD-L1 protein levels. Combining CDK4/6 inhibitor treatment with anti-PD-1 immunotherapy enhanced tumor regression and dramatically improved overall survival rates in mouse tumor models. Our study uncovered a novel molecular mechanism for regulating PD-L1 protein stability by a cell cycle kinase and revealed the potential for using combination treatment with CDK4/6 inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers.
Dana-Farber Cancer Institute
NIH
P. Sicinski: Receive a research grant from Novartis.