CRISPR Screens Identify Essential Cell Growth Mediators in BRAF Inhibitor-resistant Melanoma.

Ziyi LI; Binbin Wang; Shengqing GU; Peng Jiang; Avinash Sahu; Chen-hao Chen; Tong Han; Sailing Shi; Xiaoqing Wang; Nicole Traugh; Hailing Liu; Yin Liu; Qiu WU; Myles Brown; Tengfei Xiao; Genevieve M Boland; X Shirley Liu

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CRISPR Screens Identify Essential Cell Growth Mediators in BRAF Inhibitor-resistant Melanoma.

Author: Ziyi LI ^{1
,

2} ; Binbin WANG ^{1
,

3} ; Shengqing GU ⁴ ; Peng JIANG ⁴ ; Avinash SAHU ⁴ ; Chen-Hao CHEN ⁴ ; Tong HAN ⁵ ; Sailing SHI ⁵ ; Xiaoqing WANG ⁶ ; Nicole TRAUGH ⁶ ; Hailing LIU ⁵ ; Yin LIU ⁷ ; Qiu WU ⁵ ; Myles BROWN ^{8
,

9} ; Tengfei XIAO ¹⁰ ; Genevieve M BOLAND ^{11
,

12} ; X SHIRLEY LIU ^{13
,

14}
Author Information

1. Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
2. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
3. Department of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
4. Department of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
5. Clinical Translational Research Center, Shanghai Pulmonary Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
6. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
7. Department of Clinical Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
8. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
9. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
10. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA. Electronic address: xtfmail@gmail.com.
11. Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
12. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: GMBOLAND@partners.org.
13. Department of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
14. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address: xsliu@ds.dfci.harvard.edu.
Publication Type:Journal Article
Keywords: BRAF inhibitor; CRISPR screen; Drug resistance; Gene regulation; Melanoma
From: Genomics, Proteomics & Bioinformatics 2020;18(1):26-40
CountryChina
Language:English
Abstract: BRAF is a serine/threonine kinase that harbors activating mutations in ∼7% of human malignancies and ∼60% of melanomas. Despite initial clinical responses to BRAF inhibitors, patients frequently develop drug resistance. To identify candidate therapeutic targets for BRAF inhibitor resistant melanoma, we conduct CRISPR screens in melanoma cells harboring an activating BRAF mutation that had also acquired resistance to BRAF inhibitors. To investigate the mechanisms and pathways enabling resistance to BRAF inhibitors in melanomas, we integrate expression, ATAC-seq, and CRISPR screen data. We identify the JUN family transcription factors and the ETS family transcription factor ETV5 as key regulators of CDK6, which together enable resistance to BRAF inhibitors in melanoma cells. Our findings reveal genes contributing to resistance to a selective BRAF inhibitor PLX4720, providing new insights into gene regulation in BRAF inhibitor resistant melanoma cells.