The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer.
Purpose:The bromodomain and extra-terminal domain (BET) family proteins are epigenetic readers for acetylated histone marks. Emerging BET bromodomain inhibitors have exhibited antineoplastic activities in a wide range of human cancers through suppression of oncogenic transcription factors, including MYC. However, the preclinical activities of BET inhibitors in advanced solid cancers are moderate at best. To improve BET-targeted therapy, we interrogated mechanisms mediating resistance to BET inhibitors in colorectal cancer.Experimental Design:Using a panel of molecularly defined colorectal cancer cell lines, we examined the impact of BET inhibition on cellular proliferation and survival as well as MYC activity. We further tested the ability of inhibitors targeting the RAF/MEK/ERK (MAPK) pathway to enhance MYC suppression and circumvent intrinsic resistance to BET inhibitors. Key findings were validated using genetic approaches.Results:BET inhibitors as monotherapy moderately reduced colorectal cancer cell proliferation and MYC expression. Blockade of the MAPK pathway synergistically sensitized colorectal cancer cells to BET inhibitors, leading to potent apoptosis and MYC downregulationin vitroandin vivoA combination of JQ1 and trametinib, but neither agent alone, induced significant regression of subcutaneous colorectal cancer xenografts.Conclusions:Our findings suggest that the MAPK pathway confers intrinsic resistance to BET inhibitors in colorectal cancer and propose an effective combination strategy for the treatment of colorectal cancer.Clin Cancer Res; 23(8); 2027-37. ©2016 AACR.
Department of Neurological Surgery, Vanderbilt University, Nashville, Tennessee.
Yufang
Y
Ma
Department of Surgery, Vanderbilt University, Nashville, Tennessee.
Lihong
L
Wang
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
Leif R
LR
Neitzel
Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, Tennessee.
Sudan N
SN
Loganathan
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
Nan
N
Tang
Department of Neurological Surgery, Vanderbilt University, Nashville, Tennessee.
Lili
L
Qin
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
Emily E
EE
Crispi
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
Yan
Y
Guo
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.
Stefan
S
Knapp
Department of Surgery, Vanderbilt University, Nashville, Tennessee.
R Daniel
RD
Beauchamp
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.
Ethan
E
Lee
Department of Neurological Surgery, Vanderbilt University, Nashville, Tennessee. jialiang.wang@vanderbilt.edu.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.|Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.
Jialiang
J
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D014157:Transcription Factors
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