The Combination of CDK4/6 Inhibitor and PD-1/PD-L1 Immune Checkpoint Blocker is Expected to Enhance Treatment Efficacy

Targeted immune checkpoint protein PD1 (programmed cell death protein 1) and its ligand PD-L1 have been approved in the treatment of several cancers, and multiple drugs can be seen on the market, including “broad-spectrum anticancer drugs” such as Keytruda (anti-PD1) from MSD, Opdivo (anti-PD1) from Bristol-Myers Squibb, Bavencio (anti-PD1) co-developed by Pfizer and Merck, Tecentriq (anti-PD-L1) from Roche and Imfinzi (anti-PD-L1) from Astra Zeneca. In addition, many targeted new molecules are under study or clinical trial. However, data has shown that anti PD-1/PD-L1 treatment is still ineffective to many cancer patients. The study has shown that the response efficacy of PD-1/PD-L1 blockage is probably associated with the expression levels of PD-L1 in the tumor cells.

For ways to control PD-L1 expression and stability, a recent study on Nature titled “Cyclin D-CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance” has reported the molecular mechanism that adjusts the stability of PD-L1 via cell cycle kinase, and further proposed the possibility of enhancing the efficacy of human cancer treatment using CDK4/6 inhibitor in combination with PD-1/PD-L1 immune checkpoint blocker.

This study has found that cyclin D-CDK4 and Cullin 3SPOP E3 ligase may adjust the abundance of PD-L1 via proteasome mediated degradation. In vivo inhibition of CDK4/6 may increase the protein level of PD-L1 (which mainly relies on the inhibition of cyclin D-CDK4 mediated SPOP phosphorylation), and facilitate SPOP degradation via APC/CCdh1. however, function loss mutation in SPOP may damage ubiquitination mediated PD-L1 degradation, causing increased PD-L1 level and decreased number of tumor infiltration lymphocytes (TIL) in mice tumor and primary human prostate cancer samples. The final research results have shown that the combination of CDK4/6 inhibition treatment and anti PD-1 immunotherapy may enhance tumor regression and significantly improve the overall survival rate of tumor mice model. This provides the molecular basis for clinical response rate and efficacy of PD-1/PD-L1 blockage in cancer patients.

Reference

• 'Jinfang Zhang, Xia Bu et al.' Cyclin D–CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance. Nature. doi: 10.1038/nature25015.