| Title | Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer |
| Authors | Shu, Shaokun Wu, Hua-Jun Ge, Jennifer Y. Zeid, Rhamy Harris, Isaac S. Jovanovic, Bojana Murphy, Katherine Wang, Binbin Qiu, Xintao Endress, Jennifer E. Reyes, Jaime Lim, Klothilda Font-Tello, Alba Syamala, Sudeepa Xiao, Tengfei Chilamakuri, Chandra Sekhar Reddy Papachristou, Evangelia K. D'Santos, Clive Anand, Jayati Hinohara, Kunihiko Li, Wei McDonald, Thomas O. Luoma, Adrienne Modiste, Rebecca J. Quang-De Nguyen Michel, Brittany Cejas, Paloma Kadoch, Cigall Jaffe, Jacob D. Wucherpfennig, Kai W. Qi, Jun Liu, X. Shirley Long, Henry Brown, Myles Carroll, Jason S. Brugge, Joan S. Bradner, James Michor, Franziska Polyak, Kornelia |
| Affiliation | Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA Dana Farber Canc Inst, Dept Data Sci, Boston, MA 02215 USA Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA Dana Farber Canc Inst, Ctr Canc Evolut, Boston, MA 02215 USA Harvard Med Sch, Dept Med, Boston, MA 02115 USA Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA Harvard TH Chan Sch Publ Hlth, Boston, MA 02115 USA Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA Harvard Med Sch, Harvard MIT Div Hlth Sci & Technol, Boston, MA 02215 USA Ludwig Ctr Harvard, Boston, MA 02115 USA Univ Cambridge, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England Eli & Edythe L Broad Inst, Cambridge, MA 02142 USA Dana Farber Canc Inst, Ctr Biomed Imaging Oncol, Lurie Family Imaging Ctr, Boston, MA 02215 USA Peking Univ, Canc Hosp & Inst, Beijing 100142, Peoples R China C4 Therapeut Inc, Watertown, MA 02472 USA Tongji Univ, Shanghai Pulm Hosp, Shanghai 200092, Peoples R China Childrens Natl Med Ctr, Washington, DC 20010 USA Novartis Inst BioMed Res, Cambridge, MA 02139 USA |
| Keywords | SELECTIVE-INHIBITION SUPER-ENHANCERS CELL IDENTITY RECRUITMENT VALIDATION LANDSCAPE DISCOVERY BRD4 |
| Issue Date | 18-Jun-2020 |
| Publisher | MOLECULAR CELL |
| Abstract | BET bromodomain inhibitors (BBDIs) are candidate therapeutic agents for triple-negative breast cancer (TNBC) and other cancer types, but inherent and acquired resistance to BBDIs limits their potential clinical use. Using CRISPR and small-molecule inhibitor screens combined with comprehensive molecular profiling of BBDI response and resistance, we identified synthetic lethal interactions with BBDIs and genes that, when deleted, confer resistance. We observed synergy with regulators of cell cycle progression, YAP, AXL, and SRC signaling, and chemotherapeutic agents. We also uncovered functional similarities and differences among BRD2, BRD4, and BRD7. Although deletion of BRD2 enhances sensitivity to BBDIs, BRD7 loss leads to gain of TEAD-YAP chromatin binding and luminal features associated with BBDI resistance. Single-cell RNA-seq, ATAC-seq, and cellular barcoding analysis of BBDI responses in sensitive and resistant cell lines highlight significant heterogeneity among samples and demonstrate that BBDI resistance can be pre-existing or acquired. |
| URI | http://hdl.handle.net/20.500.11897/617347 |
| ISSN | 1097-2765 |
| DOI | 10.1016/j.molcel.2020.04.027 |
| Indexed | SCI(E) |
| Appears in Collections: | 北京肿瘤医院 |
