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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


1 Roswell Park Cancer Institute, Department of Molecular and Cellular Biology, Buffalo, USA (GRID:grid.240614.5) (ISNI:0000 0001 2181 8635)
2 Texas A&M University, Department of Chemistry, College Station, USA (GRID:grid.264756.4) (ISNI:0000 0004 4687 2082)
3 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)
4 University of California, Department of Chemistry and Biochemistry, Santa Cruz, USA (GRID:grid.205975.c) (ISNI:0000 0001 0740 6917)