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dc.contributor.author
Tong, Jingshan
dc.contributor.author
Tan, Xiao
dc.contributor.author
Song, Xiangping
dc.contributor.author
Gao, Man
dc.contributor.author
Risnik, Denise Mariel
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dc.contributor.author
Hao, Suisui
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Ermine, Kaylee
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Wang, Peng
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Li, Hua
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Huang, Yi
dc.contributor.author
Yu, Jian
dc.contributor.author
Zhang, Lin
dc.date.available
2023-02-17T01:46:22Z
dc.date.issued
2022-02
dc.identifier.citation
Tong, Jingshan; Tan, Xiao; Song, Xiangping; Gao, Man; Risnik, Denise Mariel; et al.; CDK4/6 inhibition suppresses p73 phosphorylation and activates DR5 to potentiate chemotherapy and immune checkpoint blockade; American Association for Cancer Research; Cancer Research; 82; 7; 2-2022; 1340-1352
dc.identifier.issn
0008-5472
dc.identifier.uri
http://hdl.handle.net/11336/188321
dc.description.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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Association for Cancer Research
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dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
CDK4/6
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INHIBITORS
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p73
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DR5
dc.subject.classification
Farmacología y Farmacia
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dc.subject.classification
Medicina Básica
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dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
CDK4/6 inhibition suppresses p73 phosphorylation and activates DR5 to potentiate chemotherapy and immune checkpoint blockade
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2023-02-09T16:02:00Z
dc.journal.volume
82
dc.journal.number
7
dc.journal.pagination
1340-1352
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Philadelphia
dc.description.fil
Fil: Tong, Jingshan. Univeristy of Pittsburgh. School of Medicine; Estados Unidos
dc.description.fil
Fil: Tan, Xiao. Univeristy of Pittsburgh. School of Medicine; Estados Unidos
dc.description.fil
Fil: Song, Xiangping. Univeristy of Pittsburgh. School of Medicine; Estados Unidos
dc.description.fil
Fil: Gao, Man. Univeristy of Pittsburgh. School of Medicine; Estados Unidos
dc.description.fil
Fil: Risnik, Denise Mariel. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
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Fil: Hao, Suisui. Univeristy of Pittsburgh. School of Medicine; Estados Unidos
dc.description.fil
Fil: Ermine, Kaylee. Univeristy of Pittsburgh. School of Medicine; Estados Unidos
dc.description.fil
Fil: Wang, Peng. Univeristy of Pittsburgh. School of Medicine; Estados Unidos
dc.description.fil
Fil: Li, Hua. Univeristy of Pittsburgh. School of Medicine; Estados Unidos
dc.description.fil
Fil: Huang, Yi. Univeristy of Pittsburgh. School of Medicine; Estados Unidos
dc.description.fil
Fil: Yu, Jian. Univeristy of Pittsburgh. School of Medicine; Estados Unidos
dc.description.fil
Fil: Zhang, Lin. Univeristy of Pittsburgh. School of Medicine; Estados Unidos
dc.journal.title
Cancer Research
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-21-3062
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1158/0008-5472.CAN-21-3062
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