TY - JOUR
T1 - Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma
AU - Echevarría-Vargas, Ileabett M.
AU - Reyes-Uribe, Patricia I.
AU - Guterres, Adam N.
AU - Yin, Xiangfan
AU - Kossenkov, Andrew V.
AU - Liu, Qin
AU - Zhang, Gao
AU - Krepler, Clemens
AU - Cheng, Chaoran
AU - Wei, Zhi
AU - Somasundaram, Rajasekharan
AU - Karakousis, Giorgos
AU - Xu, Wei
AU - Morrissette, Jennifer J.D.
AU - Lu, Yiling
AU - Mills, Gordon B.
AU - Sullivan, Ryan J.
AU - Benchun, Miao
AU - Frederick, Dennie T.
AU - Boland, Genevieve
AU - Flaherty, Keith T.
AU - Weeraratna, Ashani T.
AU - Herlyn, Meenhard
AU - Amaravadi, Ravi
AU - Schuchter, Lynn M.
AU - Burd, Christin E.
AU - Aplin, Andrew E.
AU - Xu, Xiaowei
AU - Villanueva, Jessie
N1 - Funding Information:
We would like to thank James Hayden and Frederick Keeney (Imaging Core Facility), Jeffrey S. Faust (Flow Cytometry), Celia Chang (Genomics Facility), and Denise DiFrancesco (Animal Core Facility) at the Wistar Institute for technical support. We thank Katrin Sproesser for providing PDX tumor samples and cell lines, Curtis Kugel for assistance with analysis of immune cells, Minu Samanta and Elene Tsopurashvili for technical assistance with immunoblots, and Regina Stoltz for assistance organizing de-identified patient data. JQ-1 was a kind gift from Dr. James Bradner (Harvard University). We are grateful to Maureen Murphy and Rugang Zhang (The Wistar Institute) for critical reading of the manuscript and Rachel Locke for editorial assistance. The RPPA analysis was performed by the MDACC RPPA core facility with support for shared resources provided by Cancer Center Support Grant (CCSG) CA016672 to MDACC. Support for RPPA was provided by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation to M. Herlyn. Support for shared resources utilized in this study was provided by Cancer Center Support Grant (CCSG) P30CA010815 to the Wistar Institute. Work in our laboratory is supported by NIH grants R01CA215733, K01CA175269, P01CA114046, P50CA174523, the American Cancer Society, the V Foundation for Cancer Research, the Melanoma Research Alliance, Melanoma Research Foundation, and the Martha W. Rogers Trust. IEV was supported by NCI NRSA T32 CA009171 Cancer Biology Training Grant to the Wistar Institute.
Funding Information:
Gordon B. Mills serves as a consultant for AstraZeneca, Blend Therapeutics, Critical Outcome Technologies Inc., HanAl Bio Korea, Illumina, Nuevolution, Pfizer, Provista Diagnostics, Roche, SignalChem Lifesciences, Symphogen, Tau Therapeutics; owns stock in Catena Pharmaceuticals, PTV Healthcare Capital, Spindle Top Capital; and has received research funding from Adelson Medical Research Foundation, AstraZeneca, Critical Outcome Technologies Inc., GSK, and Illumina. All the other authors declare no conflict of interest.
Publisher Copyright:
© 2018 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2018/5
Y1 - 2018/5
N2 - Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS-mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS-mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS-mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co-targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment-resistant tumor types.
AB - Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS-mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS-mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS-mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co-targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment-resistant tumor types.
KW - BET
KW - combination therapy
KW - drug resistance
KW - melanoma
KW - mutant NRAS
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U2 - 10.15252/emmm.201708446
DO - 10.15252/emmm.201708446
M3 - Article
C2 - 29650805
AN - SCOPUS:85045707247
SN - 1757-4676
VL - 10
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 5
M1 - e8446
ER -