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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Vydáno v:	British journal of cancer Ročník 129; číslo 8; s. 1238 - 1250
Hlavní autoři:	Kumarasamy, Vishnu, Gao, Zhe, Zhao, Bosheng, Jiang, Baishan, Rubin, Seth M, Burgess, Kevin, Witkiewicz, Agnieszka K, Knudsen, Erik S
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England Nature Publishing Group 12.10.2023
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0007-0920 1532-1827 1532-1827
DOI:	10.1038/s41416-023-02399-4