Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
pmc-release:
01
10
2021
entrez:
27
9
2021
pubmed:
28
9
2021
medline:
28
9
2021
Statut:
ppublish
Résumé
CDK4/6 inhibitors (CDK4/6i) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function, and are exquisitely sensitive to CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90/CDC37 complex. In contrast, CDK4/6i and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.
Identifiants
pubmed: 34568836
doi: 10.1038/s43018-021-00174-z
pmc: PMC8462800
mid: NIHMS1684820
pii: 10.1038/s43018-021-00174-z
doi:
Substances chimiques
HSP90 Heat-Shock Proteins
0
CDK4 protein, human
EC 2.7.11.22
CDK6 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Pagination
429-443Subventions
Organisme : NCI NIH HHS
ID : T32 CA078207
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA240362
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA196521
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA238229
Pays : United States
Organisme : NIH HHS
ID : S10 OD025132
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204314
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA233626
Pays : United States
Commentaires et corrections
Type : CommentIn
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