2. Academic Validation
  3. Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders

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

  • Nat Cancer. 2021 Apr;2(4):429-443. doi: 10.1038/s43018-021-00174-z.
Xuewei Wu 1,  Xiaobao Yang 2,  Yan Xiong 2,  Ruitong Li 3,  Takahiro Ito 3,  Tamer A Ahmed 1,  Zoi Karoulia 1,  Christos Adamopoulos 1,  Hong Wang 4,  Li Wang 5,  Ling Xie 5,  Jing Liu 2,  Beatrix Ueberheide 6,  Stuart A Aaronson 1,  Xian Chen 5,  Sean G Buchanan 4,  William R Sellers 3,  Jian Jin 2,  Poulikos I Poulikakos 7
Affiliations

Affiliations

  • 1 Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2 Department of Pharmacological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3 The Broad Institute of Harvard and MIT, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • 4 Eli Lilly and Company, Indianapolis, IN, USA.
  • 5 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
  • 6 Department of Biochemistry and Molecular Pharmacology, New York University, New York, NY, USA.
  • 7 Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Poulikos.poulikakos@mssm.edu.
PMID: 34568836 DOI: 10.1038/s43018-021-00174-z
Abstract

CDK4/6 inhibitors (CDK4/6i) 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 CDK4/6i. In contrast, tumor cells expressing both CDK4 and CDK6 have increased reliance on CDK6 to ensure cell cycle progression. We discovered that CDK4/6i 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, CDK4/6i 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 CDK4/6i and CDK4/6i-derived degraders and the need for novel inhibitors targeting the CDK4/6i-resistant, thermostable form of CDK6 for application as Cancer therapeutics.

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