EMBO Molecular Medicine (Apr 2018)
Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma
- Ileabett M Echevarría‐Vargas,
- Patricia I Reyes‐Uribe,
- Adam N Guterres,
- Xiangfan Yin,
- Andrew V Kossenkov,
- Qin Liu,
- Gao Zhang,
- Clemens Krepler,
- Chaoran Cheng,
- Zhi Wei,
- Rajasekharan Somasundaram,
- Giorgos Karakousis,
- Wei Xu,
- Jennifer JD Morrissette,
- Yiling Lu,
- Gordon B Mills,
- Ryan J Sullivan,
- Miao Benchun,
- Dennie T Frederick,
- Genevieve Boland,
- Keith T Flaherty,
- Ashani T Weeraratna,
- Meenhard Herlyn,
- Ravi Amaravadi,
- Lynn M Schuchter,
- Christin E Burd,
- Andrew E Aplin,
- Xiaowei Xu,
- Jessie Villanueva
Affiliations
- Ileabett M Echevarría‐Vargas
- Molecular & Cellular Oncogenesis Program, The Wistar Institute
- Patricia I Reyes‐Uribe
- Molecular & Cellular Oncogenesis Program, The Wistar Institute
- Adam N Guterres
- Molecular & Cellular Oncogenesis Program, The Wistar Institute
- Xiangfan Yin
- Molecular & Cellular Oncogenesis Program, The Wistar Institute
- Andrew V Kossenkov
- Molecular & Cellular Oncogenesis Program, The Wistar Institute
- Qin Liu
- Molecular & Cellular Oncogenesis Program, The Wistar Institute
- Gao Zhang
- Molecular & Cellular Oncogenesis Program, The Wistar Institute
- Clemens Krepler
- Molecular & Cellular Oncogenesis Program, The Wistar Institute
- Chaoran Cheng
- College of Computing Sciences, New Jersey Institute of Technology
- Zhi Wei
- College of Computing Sciences, New Jersey Institute of Technology
- Rajasekharan Somasundaram
- Molecular & Cellular Oncogenesis Program, The Wistar Institute
- Giorgos Karakousis
- Abramson Cancer Center, University of Pennsylvania
- Wei Xu
- Abramson Cancer Center, University of Pennsylvania
- Jennifer JD Morrissette
- Center for Personalized Diagnostics, Hospital of the University of Pennsylvania, University of Pennsylvania
- Yiling Lu
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center
- Gordon B Mills
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center
- Ryan J Sullivan
- Massachusetts General Hospital Cancer Center, Harvard Medical School
- Miao Benchun
- Massachusetts General Hospital Cancer Center, Harvard Medical School
- Dennie T Frederick
- Massachusetts General Hospital Cancer Center, Harvard Medical School
- Genevieve Boland
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School
- Keith T Flaherty
- Massachusetts General Hospital Cancer Center, Harvard Medical School
- Ashani T Weeraratna
- Melanoma Research Center, The Wistar Institute
- Meenhard Herlyn
- Molecular & Cellular Oncogenesis Program, The Wistar Institute
- Ravi Amaravadi
- Department of Surgery, Hospital of the University of Pennsylvania
- Lynn M Schuchter
- Department of Surgery, Hospital of the University of Pennsylvania
- Christin E Burd
- Departments of Molecular Genetics and Cancer Biology and Genetics, Ohio State University
- Andrew E Aplin
- Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University
- Xiaowei Xu
- Department of Surgery, Hospital of the University of Pennsylvania
- Jessie Villanueva
- Molecular & Cellular Oncogenesis Program, The Wistar Institute
- DOI
- https://doi.org/10.15252/emmm.201708446
- Journal volume & issue
-
Vol. 10,
no. 5
pp. 1 – 15
Abstract
Abstract 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.
Keywords
