Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders

Xuewei Wu, Xiaobao Yang, Yan Xiong, Ruitong Li, Takahiro Ito, Tamer A. Ahmed, Zoi Karoulia, Christos Adamopoulos, Hong Wang, Li Wang, Ling Xie, Jing Liu, Beatrix Ueberheide, Stuart A. Aaronson, Xian Chen, Sean G. Buchanan, William R. Sellers, Jian Jin, Poulikos I. Poulikakos

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Cyclin-dependent kinases (CDKs) 4 and 6 inhibitors (CDK4/6is) are effective in metastatic breast cancer, but they have been only modestly effective in most other tumor types. Here we show that tumors expressing low CDK6 rely on CDK4 function and are exquisitely sensitive to CDK4/6is. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6is and CDK4/6 degraders potently bind and inhibit CDK6 selectively in tumors in which CDK6 is highly thermo-unstable and strongly associated with the HSP90–CDC37 complex. In contrast, CDK4/6is and CDK4/6 degraders are ineffective in antagonizing tumor cells expressing thermostable CDK6, due to their weaker binding to CDK6 in these cells. Thus, we uncover a general mechanism of intrinsic resistance to CDK4/6is and CDK4/6i-derived degraders and the need for new inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as cancer therapeutics.

Original languageEnglish
Pages (from-to)429-443
Number of pages15
JournalNature Cancer
Volume2
Issue number4
DOIs
StatePublished - Apr 2021

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