Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders
Xuewei Wu1, Xiaobao Yang2, Yan Xiong2
1Department of Oncological Sciences, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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.
Insights
CDK4/6 inhibitors show limited efficacy in many cancers. This study reveals that tumors with low CDK6 are sensitive to these inhibitors, while those with thermostable CDK6 are resistant, necessitating new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are established treatments for metastatic breast cancer.
- Their efficacy is limited in many other cancer types, suggesting underlying resistance mechanisms.
Purpose of the Study:
- To elucidate the mechanisms of intrinsic resistance to CDK4/6 inhibitors and related degraders.
- To identify factors determining differential sensitivity to CDK4/6 inhibition across tumor types.
Main Methods:
- Analysis of tumor cell dependency on CDK4 versus CDK6.
- Investigation of CDK6 thermostability and its association with the HSP90/CDC37 complex.
- Assessment of CDK4/6i and CDK4/6 degrader binding and inhibitory activity.
Main Results:
- Tumors with low CDK6 expression are highly sensitive to CDK4/6i due to reliance on CDK4.
- Tumor cells expressing both CDK4 and CDK6 depend more on CDK6 for cell cycle progression.
- CDK4/6i and degraders are effective against tumors with thermo-unstable CDK6 but ineffective against those with thermostable CDK6.
- Resistance is linked to weaker binding of inhibitors to thermostable CDK6.
Conclusions:
- Tumor cell CDK6 thermostability dictates intrinsic resistance to CDK4/6 inhibitors and degraders.
- A novel mechanism of resistance involves the association of thermo-unstable CDK6 with the HSP90/CDC37 complex.
- Development of novel inhibitors targeting the thermostable form of CDK6 is crucial for overcoming resistance and expanding therapeutic applications.
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