Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer PMID: 32416067

ADC Targets in Oncology

2026-04-10

Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer

Mol Cell. 2020 Jun 18;78(6):1096-1113.e8. doi: 10.1016/j.molcel.2020.04.027.

Shaokun Shu ¹ , Hua-Jun Wu ² , Jennifer Y Ge ³ , Rhamy Zeid ⁴ , Isaac S Harris ⁵ , Bojana Jovanović ⁶ , Katherine Murphy ⁴ , Binbin Wang ⁷ , Xintao Qiu ⁸ , Jennifer E Endress ⁵ , Jaime Reyes ⁴ , Klothilda Lim ⁸ , Alba Font-Tello ⁸ , Sudeepa Syamala ⁸ , Tengfei Xiao ⁷ , Chandra Sekhar Reddy Chilamakuri ⁹ , Evangelia K Papachristou ⁹ , Clive D'Santos ⁹ , Jayati Anand ⁴ , Kunihiko Hinohara ¹ , Wei Li ¹⁰ , Thomas O McDonald ¹¹ , Adrienne Luoma ¹² , Rebecca J Modiste ¹³ , Quang-De Nguyen ¹³ , Brittany Michel ¹⁴ , Paloma Cejas ⁸ , Cigall Kadoch ¹⁵ , Jacob D Jaffe ¹⁶ , Kai W Wucherpfennig ¹² , Jun Qi ⁴ , X Shirley Liu ¹⁷ , Henry Long ⁸ , Myles Brown ¹⁸ , Jason S Carroll ⁹ , Joan S Brugge ⁵ , James Bradner ¹ , Franziska Michor ¹⁹ , Kornelia Polyak ²⁰

Affiliations

1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
2. Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02215, USA.
4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
5. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA.
6. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA.
7. Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
8. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
9. Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
10. Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
11. Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
12. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
13. Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
14. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
15. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA.
16. The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA.
17. Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
18. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA.
19. Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Ludwig Center at Harvard, Boston, MA 02115, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA. Electronic address: [email protected].
20. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA. Electronic address: [email protected].

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.

Keywords

ATAC-seq; BET bromodomain inhibitors; CRISPR screen; ChIP-seq; cellular barcoding; single cell ATAC-seq; single cell RNA-seq; small molecule inhibitor screen; therapeutic resistance; triple-negative breast cancer.