PROTAC-mediated CDK degradation differentially impacts cancer cell cycles due to heterogeneity in kinase dependencies

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We investigate whether the differential requirements of CDKs in multiple cell lines function as determinant of response to pharmacological agents that...

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Bibliographic Details
Published in:British journal of cancer Vol. 129; no. 8; pp. 1238 - 1250
Main Authors: Kumarasamy, Vishnu, Gao, Zhe, Zhao, Bosheng, Jiang, Baishan, Rubin, Seth M, Burgess, Kevin, Witkiewicz, Agnieszka K, Knudsen, Erik S
Format: Journal Article
Language:English
Published: England Nature Publishing Group 12.10.2023
Subjects:
Animals
Cell activation
Cell cycle
Cell Cycle - drug effects
Cell Line, Tumor
Cell proliferation
Cell Proliferation - drug effects
Chimeras
Cyclin E
Cyclin-dependent kinase 2
Cyclin-dependent kinase 4
Cyclin-Dependent Kinase 4 - antagonists & inhibitors
Cyclin-Dependent Kinase 4 - metabolism
Cyclin-Dependent Kinase 6 - antagonists & inhibitors
Cyclin-Dependent Kinase 6 - metabolism
Cyclin-dependent kinases
Humans
INK4a protein
Kinases
Mice
Organoids
p16 Protein
Piperazines - pharmacology
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Proteolysis
Proteolysis - drug effects
Pyridines - chemistry
Pyridines - pharmacology
Thalidomide - analogs & derivatives
Thalidomide - pharmacology
Tumors
Xenograft Model Antitumor Assays
ISSN:0007-0920, 1532-1827, 1532-1827
Online Access:Get full text
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Summary:Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition yields differential cellular responses in multiple tumor models due to redundancy in cell cycle. We investigate whether the differential requirements of CDKs in multiple cell lines function as determinant of response to pharmacological agents that target these kinases. We utilized proteolysis-targeted chimeras (PROTACs) that are conjugated with palbociclib (Palbo-PROTAC) to degrade both CDK4 and CDK6. FN-POM was synthesized by chemically conjugating pomalidomide moiety with a multi-kinase inhibitor, FN-1501. Patient derived PDAC organoids and PDX model were utilized to investigate the effect of FN-POM in combination with palbociclib. Palbo-PROTAC mediates differential impact on cell cycle in different tumor models, indicating that the dependencies to CDK4 and 6 kinases are heterogenous. Cyclin E overexpression uncouples cell cycle from CDK4/6 and drives resistance to palbo-PROTAC. Elevated expression of P16INK4A antagonizes PROTAC-mediated degradation of CDK4 and 6. FN-POM degrades cyclin E and CDK2 and inhibits cell cycle progression in P16INK4A-high tumor models. Combination of palbociclib and FN-POM cooperatively inhibit tumor cell proliferation via RB activation. Resistance to CDK4/6 inhibition could be overcome by pharmacologically limiting Cyclin E/CDK2 complex and proves to be a potential therapeutic approach.
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ISSN:0007-0920
1532-1827
1532-1827
DOI:10.1038/s41416-023-02399-4