作者
April C. Watt,Paloma Cejas,Molly J. DeCristo,Otto Metzger‐Filho,Enid Y.N. Lam,Xintao Qiu,Haley BrinJones,Nikolas Kesten,Rhiannon Coulson,Alba Font-Tello,Klothilda Lim,Raga Vadhi,Veerle W. Daniëls,Joan Montero,Len Taing,Clifford A. Meyer,Omer Gilan,Charles C. Bell,Keegan Korthauer,Claudia Giambartolomei,Bogdan Paşaniuc,Ji Heui Seo,Matthew L. Freedman,Cynthia Ma,Matthew J. Ellis,Ian E. Krop,Eric P. Winer,Anthony Letaï,Myles Brown,Mark A. Dawson,Henry W. Long,Jean J. Zhao,Shom Goel
摘要
Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses, and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that is enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several Activator Protein-1 (AP-1) transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors.