Publications

by Keyword: Cancer therapy


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Watt, April C., Cejas, Paloma, DeCristo, Molly J., Metzger-Filho, Otto, Lam, Enid Y. N., Qiu, Xintao, BrinJones, Haley, Kesten, Nikolas, Coulson, Rhiannon, Font-Tello, Alba, Lim, Klothilda, Vadhi, Raga, Daniels, Veerle W., Montero, Joan, Taing, Len, Meyer, Clifford A., Gilan, Omer, Bell, Charles C., Korthauer, Keegan D., Giambartolomei, Claudia, Pasaniuc, Bogdan, Seo, Ji-Heui, Freedman, Matthew L., Ma, Cynthia, Ellis, Matthew J., Krop, Ian, Winer, Eric, Letai, Anthony, Brown, Myles, Dawson, Mark A., Long, Henry W., Zhao, Jean J., Goel, Shom, (2021). CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity Nature Cancer 2, 34-48

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 are enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several activator protein-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.

Keywords: Breast cancer, Cancer, Cancer therapy, Epigenetics