title: Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma.
abstract: The discovery of potent inhibitors of the BRAF proto-oncogene has revolutionized therapy for melanoma harboring mutations in BRAF, yet NRAS-mutant melanoma remains without an effective therapy. Because direct pharmacological inhibition of the RAS proto-oncogene has thus far been unsuccessful, we explored systems biology approaches to identify synergistic drug combination(s) that can mimic RAS inhibition. Here, leveraging an inducible mouse model of NRAS-mutant melanoma, we show that pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) activates apoptosis but not cell-cycle arrest, which is in contrast to complete genetic neuroblastoma RAS homolog (NRAS) extinction, which triggers both of these effects. Network modeling pinpointed cyclin-dependent kinase 4 (CDK4) as a key driver of this differential phenotype. Accordingly, combined pharmacological inhibition of MEK and CDK4 in vivo led to substantial synergy in therapeutic efficacy. We suggest a gradient model of oncogenic NRAS signaling in which the output is gated, resulting in the decoupling of discrete downstream biological phenotypes as a result of incomplete inhibition. Such a gated signaling model offers a new framework to identify nonobvious coextinction target(s) for combined pharmacological inhibition in NRAS-mutant melanomas.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Kwong
authors.forename: James C
authors.initials: JC
authors.lastname: Costello
authors.forename: Huiyun
authors.initials: H
authors.lastname: Liu
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Helms
authors.forename: Aliete E
authors.initials: AE
authors.lastname: Langsdorf
authors.forename: David
authors.initials: D
authors.lastname: Jakubosky
authors.forename: Giannicola
authors.initials: G
authors.lastname: Genovese
authors.forename: Florian L
authors.initials: FL
authors.lastname: Muller
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Jeong
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Bender
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Chu
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D011905:Genes, ras; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051358:Cyclin-Dependent Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D004318:Doxycycline