Journal article
CDK4/6 Inhibition Suppresses p73 Phosphorylation and Activates DR5 to Potentiate Chemotherapy and Immune Checkpoint Blockade
Cancer research (Chicago, Ill.), Vol.82(7), pp.1340-1352
04/01/2022
DOI: 10.1158/0008-5472.CAN-21-3062
PMCID: PMC8983601
PMID: 35149588
Abstract
Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is a successful therapeutic approach against breast and other solid tumors. 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.
Significance: 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
Details
- Title: Subtitle
- CDK4/6 Inhibition Suppresses p73 Phosphorylation and Activates DR5 to Potentiate Chemotherapy and Immune Checkpoint Blockade
- Creators
- Jingshan Tong - University of PittsburghXiao Tan - University of PittsburghXiangping Song - University of PittsburghMan Gao - University of PittsburghDenise Risnik - University of PittsburghSuisui Hao - University of PittsburghKaylee Ermine - University of PittsburghPeng Wang - University of PittsburghHua Li - University of PittsburghYi Huang - University of PittsburghJian Yu - University of PittsburghLin Zhang - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.82(7), pp.1340-1352
- DOI
- 10.1158/0008-5472.CAN-21-3062
- PMID
- 35149588
- PMCID
- PMC8983601
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 13
- Grant note
- R01CA203028; R01CA217141; R01CA236271; R01CA247231; R01CA248112; U19AI068021; R01CA215481; R01CA260357; T32GM133332; P30CA047904 / U.S. NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 04/01/2022
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383902402771
Metrics
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