{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Tong J"],"funding":["NIAID NIH HHS","NCI NIH HHS","NIH","NIGMS NIH HHS"],"pagination":["1340-1352"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8983601"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["82(7)"],"pubmed_abstract":["Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is a successful therapeutic approach against breast and other solid tumors. Inhibition of CDK4/6 halts cell cycle progression and promotes antitumor immunity. However, the mechanisms underlying the antitumor activity of CDK4/6 inhibitors are not fully understood. We found that CDK4/6 bind and phosphorylate the p53 family member p73 at threonine 86, which sequesters p73 in the cytoplasm. Inhibition of CDK4/6 led to dephosphorylation and nuclear translocation of p73, which transcriptionally activated death receptor 5 (DR5), a cytokine receptor and key component of the extrinsic apoptotic pathway. p73-mediated induction of DR5 by CDK4/6 inhibitors promoted immunogenic cell death of cancer cells. Deletion of DR5 in cancer cells in vitro and in vivo abrogated the potentiating effects of CDK4/6 inhibitors on immune cytokine TRAIL, 5-fluorouracil chemotherapy, and anti-PD-1 immunotherapy. Together, these results reveal a previously unrecognized consequence of CDK4/6 inhibition, which may be critical for potentiating the killing and immunogenic effects on cancer cells.<h4>Significance</h4>This work demonstrates how inhibition of CDK4/6 sensitizes cancer cells to chemotherapy and immune checkpoint blockade and may provide a new molecular marker for improving CDK4/6-targeted cancer therapies. See related commentary by Frank, p. 1170."],"journal":["Cancer research"],"pubmed_title":["CDK4/6 Inhibition Suppresses p73 Phosphorylation and Activates DR5 to Potentiate Chemotherapy and Immune Checkpoint Blockade."],"pmcid":["PMC8983601"],"funding_grant_id":["R01CA247231","R01CA203028","R01CA248112","R01 CA236271","T32 GM133332","P30CA047904","R01 CA215481","R01CA217141","R01 CA217141","R01CA215481","U19AI068021","U19 AI068021","P30 CA047904","R01 CA248112","R01CA236271","R01 CA247231","T32GM133332","R01 CA203028","R01 CA260357","R01CA260357"],"pubmed_authors":["Li H","Risnik D","Wang P","Tan X","Gao M","Huang Y","Tong J","Ermine K","Zhang L","Song X","Yu J","Hao S"],"additional_accession":[]},"is_claimable":false,"name":"CDK4/6 Inhibition Suppresses p73 Phosphorylation and Activates DR5 to Potentiate Chemotherapy and Immune Checkpoint Blockade.","description":"Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is a successful therapeutic approach against breast and other solid tumors. Inhibition of CDK4/6 halts cell cycle progression and promotes antitumor immunity. However, the mechanisms underlying the antitumor activity of CDK4/6 inhibitors are not fully understood. We found that CDK4/6 bind and phosphorylate the p53 family member p73 at threonine 86, which sequesters p73 in the cytoplasm. Inhibition of CDK4/6 led to dephosphorylation and nuclear translocation of p73, which transcriptionally activated death receptor 5 (DR5), a cytokine receptor and key component of the extrinsic apoptotic pathway. p73-mediated induction of DR5 by CDK4/6 inhibitors promoted immunogenic cell death of cancer cells. Deletion of DR5 in cancer cells in vitro and in vivo abrogated the potentiating effects of CDK4/6 inhibitors on immune cytokine TRAIL, 5-fluorouracil chemotherapy, and anti-PD-1 immunotherapy. Together, these results reveal a previously unrecognized consequence of CDK4/6 inhibition, which may be critical for potentiating the killing and immunogenic effects on cancer cells.<h4>Significance</h4>This work demonstrates how inhibition of CDK4/6 sensitizes cancer cells to chemotherapy and immune checkpoint blockade and may provide a new molecular marker for improving CDK4/6-targeted cancer therapies. See related commentary by Frank, p. 1170.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Apr","modification":"2024-10-16T10:49:06.84Z","creation":"2024-10-16T10:49:06.84Z"},"accession":"S-EPMC8983601","cross_references":{"pubmed":["35149588"],"doi":["10.1158/0008-5472.can-21-3062","10.1158/0008-5472.CAN-21-3062"]}}