4.5 Article

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

Journal

NATURE CANCER
Volume 2, Issue 4, Pages 429-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s43018-021-00174-z

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Categories

Funding

  1. US National Institutes of Health (NIH)/NCI [R01CA204314, R01 CA240362, R01CA238229]
  2. Irma T. Hirschl Trust
  3. Manhasset Women's Coalition against Breast Cancer
  4. Breast Cancer Alliance
  5. Melanoma Research Foundation
  6. Melanoma Research Alliance
  7. Tisch Cancer Institute developmental awards
  8. 2017 Robin Chemers Neustein Postdoctoral Fellowship
  9. NIH [1R01CA233626, P30CA196521, R01-GM133107]
  10. Ludwig Center at Harvard
  11. Department of Defense Peer Reviewed Cancer Research Program Horizon Award [W81XWH-19-1-0271]
  12. Breast Cancer Research Foundation
  13. Icahn School of Medicine at Mount Sinai
  14. NIH SIG grant [1S10OD025132-01A1]
  15. [T32CA078207]

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Research shows that CDK4/6 inhibitors are particularly effective in tumors with low CDK6 expression, while tumors expressing both CDK4 and CDK6 rely more on CDK6. The study reveals that CDK4/6is and CDK4/6 degraders selectively inhibit CDK6 in tumors where it is highly thermo-unstable and associated with the HSP90-CDC37 complex, but are ineffective in tumor cells expressing thermostable CDK6.
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. Poulikakos and colleagues demonstrate that thermostable CDK6 complexes promote resistance to therapeutic targeting of CDK4/6 in cancer.

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