Content area

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

Resistance to CDK4/6 inhibition could be overcome by pharmacologically limiting Cyclin E/CDK2 complex and proves to be a potential therapeutic approach.

Details

Title
PROTAC-mediated CDK degradation differentially impacts cancer cell cycles due to heterogeneity in kinase dependencies
Author
Kumarasamy, Vishnu 1 ; Gao, Zhe 2 ; Zhao, Bosheng 2 ; Jiang, Baishan 3   VIAFID ORCID Logo  ; Rubin, Seth M. 4 ; Burgess, Kevin 2 ; Witkiewicz, Agnieszka K. 1 ; Knudsen, Erik S. 1   VIAFID ORCID Logo 

 Roswell Park Cancer Institute, Department of Molecular and Cellular Biology, Buffalo, USA (GRID:grid.240614.5) (ISNI:0000 0001 2181 8635) 
 Texas A&M University, Department of Chemistry, College Station, USA (GRID:grid.264756.4) (ISNI:0000 0004 4687 2082) 
 Zhongnan Hospital of Wuhan University, Wuhan University, Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Wuhan, China (GRID:grid.49470.3e) (ISNI:0000 0001 2331 6153) 
 University of California, Department of Chemistry and Biochemistry, Santa Cruz, USA (GRID:grid.205975.c) (ISNI:0000 0001 0740 6917) 
Pages
1238-1250
Publication year
2023
Publication date
Oct 2023
Publisher
Nature Publishing Group
ISSN
00070920
e-ISSN
15321827
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2876764043
Copyright
© The Author(s), under exclusive licence to Springer Nature Limited 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.