PROTAC-mediated CDK degradation differentially impacts cancer cell cycles due to heterogeneity in kinase dependencies
Menée à l'aide de lignées cellulaires, d'organoïdes d'adénocarcinome canalaire du pancréas et de xénogreffes sur des modèles murins, cette étude démontre que la dégradation des kinases CDK4/6 induite par les PROTACs (proteolysis-targeted chimeras) affecte différemment le cycle des cellules cancéreuses en raison du niveau de dépendance aux CDK qui diffère selon les cellules puis met en évidence l'intérêt thérapeutique d'un nouveau PROTAC liant un groupe pomalidomide à un inhibiteur multikinase qui cible préférentiellement le récepteur FLT3 et les complexes protéiques cycline D1/CDK4 et cycline A/CDK2
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.