由于细胞周期中的冗余，细胞周期依赖性激酶4和6（CDK4/6）抑制对多种肿瘤模型产生差异性的细胞反应。我们研究CDK在多种细胞系中的差异性需求是否作为靶向这些激酶的药物作用的决定因素。我们利用与帕博西利（Palbo-PROTAC）结合的蛋白酶降解靶向嵌合体（PROTACs）来降解CDK4和CDK6。化学上将Pomalidomide结合在多激酶抑制剂FN-1501上，合成了FN-POM。我们利用患者源性PDAC器官样和PDX模型来研究FN-POM与帕博西利的联合作用。Palbo-PROTAC在不同的肿瘤模型中对细胞周期产生差异性影响，表明对CDK4和6激酶的依赖性是异质的。环E过表达使细胞周期与CDK4/6脱耦，并导致对帕博西利的抵抗。P16INK4A的高表达对PROTAC介导的CDK4和6的降解起到拮抗作用。FN-POM降解环E和CDK2，并抑制P16INK4A高表达的肿瘤模型中的细胞周期进程。帕博西利和FN-POM的联合应用通过RB的激活合作抑制肿瘤细胞增殖。通过药物限制环E/CDK2复合物，CDK4/6抑制的耐药性可以被克服，这被证明是一种潜在的治疗方法。© 2023. 作者以独家许可给Springer Nature Limited。

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.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.