Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence
Katherine R. Singleton,
Lorin Crawford,
Elizabeth Tsui,
Haley E. Manchester,
Ophelia Maertens,
Xiaojing Liu,
Maria V. Liberti,
Anniefer N. Magpusao,
Elizabeth M. Stein,
Jennifer P. Tingley,
Dennie T. Frederick,
Genevieve M. Boland,
Keith T. Flaherty,
Shannon J. McCall,
Clemens Krepler,
Katrin Sproesser,
Meenhard Herlyn,
Drew J. Adams,
Jason W. Locasale,
Karen Cichowski,
Sayan Mukherjee,
Kris C. Wood
Affiliations
Katherine R. Singleton
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
Lorin Crawford
Department of Statistical Science, Duke University, Durham, NC 27708, USA
Elizabeth Tsui
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
Haley E. Manchester
Genetics Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
Ophelia Maertens
Genetics Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
Xiaojing Liu
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
Maria V. Liberti
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
Anniefer N. Magpusao
Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA
Elizabeth M. Stein
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
Jennifer P. Tingley
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
Dennie T. Frederick
Harvard Medical School, Boston, MA 02115, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA
Genevieve M. Boland
Harvard Medical School, Boston, MA 02115, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA
Keith T. Flaherty
Harvard Medical School, Boston, MA 02115, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA
Shannon J. McCall
Department of Pathology, Duke University, Durham, NC 27710, USA
Clemens Krepler
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA
Katrin Sproesser
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA
Meenhard Herlyn
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA
Drew J. Adams
Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA
Jason W. Locasale
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
Karen Cichowski
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
Sayan Mukherjee
Department of Statistical Science, Duke University, Durham, NC 27708, USA; Departments of Mathematics and Computer Science, Duke University, Durham, NC 27708, USA
Kris C. Wood
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Corresponding author
Summary: 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. : Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, but by combining statistical modeling of tumor data with functional interrogation of resistance models, Singleton et al. show that these pathways converge to activate MYC. BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, informing therapies that select against resistance. Keywords: melanoma, cancer therapeutics, therapeutic resistance, signaling networks, MYC, metabolism, synthetic lethality
