PROTAC-mediated CDK degradation differentially impacts cancer cell cycles due to heterogeneity in kinase dependencies,British Journal of Cancer

当前位置： X-MOL 学术 › Br. J. Cancer › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

PROTAC-mediated CDK degradation differentially impacts cancer cell cycles due to heterogeneity in kinase dependencies
British Journal of Cancer ( IF 6.4 ) Pub Date : 2023-08-25 , DOI: 10.1038/s41416-023-02399-4
Vishnu Kumarasamy ₁ , Zhe Gao ₂ , Bosheng Zhao ₂ , Baishan Jiang ₃ , Seth M Rubin ₄ , Kevin Burgess ₂ , Agnieszka K Witkiewicz ₁ , Erik S Knudsen ₁

Affiliation

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.

中文翻译：

由于激酶依赖性的异质性，PROTAC 介导的 CDK 降解对癌细胞周期有不同的影响

背景

由于细胞周期冗余，细胞周期蛋白依赖性激酶 4 和 6 (CDK4/6) 抑制在多种肿瘤模型中产生不同的细胞反应。我们研究了多种细胞系中 CDK 的不同需求是否决定了对靶向这些激酶的药物的反应。

方法

我们利用与 palbociclib (Palbo-PROTAC) 缀合的蛋白水解靶向嵌合体 (PROTAC) 来降解 CDK4 和 CDK6。 FN-POM 通过化学缀合泊马度胺部分与多激酶抑制剂 FN-1501 合成。利用患者衍生的 PDAC 类器官和 PDX 模型来研究 FN-POM 与 Palbociclib 联合使用的效果。

结果

Palbo-PROTAC 在不同肿瘤模型中介导对细胞周期的不同影响，表明对 CDK4 和 6 激酶的依赖性是异质的。 Cyclin E 过度表达使细胞周期与 CDK4/6 解偶联，并驱动对 palbo-PROTAC 的耐药性。 P16INK4A 表达升高会拮抗 PROTAC 介导的 CDK4 和 6 降解。FN-POM 降解细胞周期蛋白 E 和 CDK2，并抑制 P16INK4A 高肿瘤模型中的细胞周期进程。 palbociclib 和 FN-POM 的组合通过 RB 激活协同抑制肿瘤细胞增殖。