2. Academic Validation
  3. Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence

Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence

  • Cell Rep. 2017 Dec 5;21(10):2796-2812. doi: 10.1016/j.celrep.2017.11.022.
Katherine R Singleton 1,  Lorin Crawford 2,  Elizabeth Tsui 1,  Haley E Manchester 3,  Ophelia Maertens 3,  Xiaojing Liu 1,  Maria V Liberti 4,  Anniefer N Magpusao 5,  Elizabeth M Stein 1,  Jennifer P Tingley 1,  Dennie T Frederick 6,  Genevieve M Boland 6,  Keith T Flaherty 6,  Shannon J McCall 7,  Clemens Krepler 8,  Katrin Sproesser 8,  Meenhard Herlyn 8,  Drew J Adams 5,  Jason W Locasale 1,  Karen Cichowski 9,  Sayan Mukherjee 10,  Kris C Wood 11
Affiliations

Affiliations

  • 1 Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
  • 2 Department of Statistical Science, Duke University, Durham, NC 27708, USA.
  • 3 Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
  • 4 Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Molecular Biology and Genetics, Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA.
  • 5 Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA.
  • 6 Harvard Medical School, Boston, MA 02115, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
  • 7 Department of Pathology, Duke University, Durham, NC 27710, USA.
  • 8 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
  • 9 Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Boston, MA 02115, USA.
  • 10 Department of Statistical Science, Duke University, Durham, NC 27708, USA; Departments of Mathematics and Computer Science, Duke University, Durham, NC 27708, USA.
  • 11 Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. Electronic address: [email protected].
PMID: 29212027 DOI: 10.1016/j.celrep.2017.11.022
Abstract

Diverse pathways drive resistance to BRaf/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-Myc (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression. Critically, MYC activation was necessary and sufficient for resistance, and suppression of MYC activity using genetic approaches or BET bromodomain inhibition was sufficient to resensitize cells and delay BRAFi resistance. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including Src family and c-Kit tyrosine kinases, as well as glucose, glutamine, and serine metabolic pathways. These insights enable the design of combination therapies that select against resistance evolution.

Keywords

MYC; cancer therapeutics; melanoma; metabolism; signaling networks; synthetic lethality; therapeutic resistance.

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