Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders
Menée in vitro et à l'aide de modèle murins, cette étude démontre que la réponse des cellules cancéreuses aux inhibiteurs et agents dégradeurs de kinases CDK4/6 dépend de la liaison entre le complexe protéique HSP90 et la kinase 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.
Nature Cancer 2021