2. Academic Validation
  3. Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma

Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma

  • EMBO Mol Med. 2018 May;10(5):e8446. doi: 10.15252/emmm.201708446.
Ileabett M Echevarría-Vargas 1,  Patricia I Reyes-Uribe 1,  Adam N Guterres 1,  Xiangfan Yin 1,  Andrew V Kossenkov 1,  Qin Liu 1,  Gao Zhang 1,  Clemens Krepler 1,  Chaoran Cheng 2,  Zhi Wei 2,  Rajasekharan Somasundaram 1,  Giorgos Karakousis 3 4,  Wei Xu 3,  Jennifer Jd Morrissette 5 6,  Yiling Lu 7,  Gordon B Mills 7,  Ryan J Sullivan 8,  Miao Benchun 8,  Dennie T Frederick 8,  Genevieve Boland 9,  Keith T Flaherty 8,  Ashani T Weeraratna 10 11,  Meenhard Herlyn 1 10,  Ravi Amaravadi 4 12,  Lynn M Schuchter 4 12,  Christin E Burd 13,  Andrew E Aplin 14,  Xiaowei Xu 4 7,  Jessie Villanueva 15 10
Affiliations

Affiliations

  • 1 Molecular & Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
  • 2 College of Computing Sciences, New Jersey Institute of Technology, Newark, NJ, USA.
  • 3 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
  • 4 Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
  • 5 Center for Personalized Diagnostics, Hospital of the University of Pennsylvania University of Pennsylvania, Philadelphia, PA, USA.
  • 6 Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
  • 7 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 8 Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • 9 Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 10 Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
  • 11 Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.
  • 12 Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
  • 13 Departments of Molecular Genetics and Cancer Biology and Genetics, Ohio State University, Columbus, OH, USA.
  • 14 Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
  • 15 Molecular & Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA jvillanueva@wistar.org.
PMID: 29650805 DOI: 10.15252/emmm.201708446
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

BET; combination therapy; drug resistance; melanoma; mutant NRAS.

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