@article{12214ad58d5b4af590be15a8c4e5400a,
title = "CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity",
abstract = "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.",
author = "Watt, {April C.} and Paloma Cejas and DeCristo, {Molly J.} and Otto Metzger-Filho and Lam, {Enid Y.N.} and Xintao Qiu and Haley BrinJones and Nikolas Kesten and Rhiannon Coulson and Alba Font-Tello and Klothilda Lim and Raga Vadhi and Daniels, {Veerle W.} and Joan Montero and Len Taing and Meyer, {Clifford A.} and Omer Gilan and Bell, {Charles C.} and Korthauer, {Keegan D.} and Claudia Giambartolomei and Bogdan Pasaniuc and Seo, {Ji Heui} and Freedman, {Matthew L.} and Cynthia Ma and Ellis, {Matthew J.} and Ian Krop and Eric Winer and Anthony Letai and Myles Brown and Dawson, {Mark A.} and Long, {Henry W.} and Zhao, {Jean J.} and Shom Goel",
note = "Funding Information: This work is supported by the National Health and Medical Research Council of Australia (Investigator Grant GNT1177357 to S.G.); Susan G. Komen for the Cure (to I.K. and M.B. and CCR18547966 to S.G.); the Breast Cancer Alliance (Young Investigator Grant to S.G.); the Royal Australasian College of Physicians (Research Establishment Fellowship to S.G.); Eli Lilly and Co (to S.G.); the NIH/NCI (P50 CA168504 to S.G., I.K., E.W. and J.J.Z.; R35 CA210057 to J.J.Z.; P50 CA165962-06A1 to J.J.Z.; P01CA080111 to M.B.; R01CA193910 to M.L.F.; R02HG005220 to K.D.K. (PI Rafael A. Irizarry), R01GM083084 to K.D.K. (PI Rafael A. Irizarry), U41HG004059 to K.D.K. (PI Martin T. Morgan)); the US Department of Defense CDMRP (W81XWH-18-1-0491 to J.J.Z.); the Breast Cancer Research Foundation (BCRF-18-179 to J.J.Z. and O.M.-F.), the Ministry of Economy and Competitiveness (Instituto de Salud Carlos III) PI18-01604 to P.C.; the Chan Zuckerberg Initiative (DAF grant 2018-183142 to K.D.K. (PI Rafael A. Irizarry)); Stand Up To Cancer (SU2C) and The V Foundation (TVF) SU2C-TVF Convergence Scholar Awards (D2015-037 to J.M.); Ramon y Cajal Programme, Ministerio de Economia y Competitividad (RYC-2015-18357 to J.M.); Terri Brodeur Breast Cancer Foundation (to V.W.D.); and the European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme (Marie Sk{\l}odowska-Curie grant agreement no. 754490 to C.G. and the MINDED project). Funding Information: S.G. is the recipient of research funding from Eli Lilly and Co., which has been used to support a part of this work. S.G. has served as a paid advisory board member for Eli Lilly and Co., G1 Therapeutics, Pfizer and Novartis. S.G. also conducts laboratory research sponsored by G1 Therapeutics and clinical research sponsored by Eli Lilly and Co. and by Novartis. J.J.Z. is founder and board director of Crimson Biotech and Geode Therapeutics. J.M. is a consultant for Oncoheroes Biosciences and Vivid Biosciences. M.B. receives sponsored research support from Novartis. M.B. is a consultant to H3 Biomedicine and serves on the SAB of Kronos Bio and GV20 Therapeutics. C.M. is a consultant for Pfizer, Novartis, Seattle Genetics and Eli Lilly and Co. and receives institutional research funding from Pfizer and Puma. I.K. receives institutional research funding and grants from Genentech/Roche and Pfizer. I.K. is an advisory board participant, consultant and has received honoraria from Daiichi/Sankyo, Macrogenics and Genentech/Roche. I.K. is an advisory board participant and has received honoraria from Context Therapeutics, Taiho Oncology and Seattle Genetics. I.K. is a data monitoring board member at Novartis. E.W. is a consultant at and has received honoraria from Carrick Therapeutics, DragonFly, Genentech/Roche, Genomic Health, GSK, Jounce, Eli Lilly and Co., Seattle Genetics and Merck. E.W. is a scientific advisory board member and has received honoraria from Leap. M.E. has patents and receives royalties from prosigna/Nanostring. O.M.-F. receives institutional research funding from AbbVie, Genentech, Roche and Pfizer, and has received honoraria from Roche. M.A.D. has been a member of the advisory boards for CTX CRC, Storm Therapeutics, Celgene and Cambridge Epigenetix. The Dawson laboratory receives research funding from CTX CRC. All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = jan,
doi = "10.1038/s43018-020-00135-y",
language = "English",
volume = "2",
pages = "34--48",
journal = "Nature Cancer",
issn = "2662-1347",
publisher = "Nature Publishing Group",
number = "1",
}
