Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma

• Published in: Nature medicine Vol. 18; no. 10; pp. 1503 - 1510
• Main Authors: Kwong, Lawrence N, Costello, James C, Liu, Huiyun, Jiang, Shan, Helms, Timothy L, Langsdorf, Aliete E, Jakubosky, David, Genovese, Giannicola, Muller, Florian L, Jeong, Joseph H, Bender, Ryan P, Chu, Gerald C, Flaherty, Keith T, Wargo, Jennifer A, Collins, James J, Chin, Lynda
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.10.2012
• Subjects: Analysis; Animals; Apoptosis; Apoptosis - drug effects; Benzimidazoles - pharmacology; Cancer therapies; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival; Cellular signal transduction; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - metabolism; Doxycycline - pharmacology; Drug therapy; Female; Genes, ras; Genetic aspects; Health aspects; Humans; Inhibition; Inhibitor drugs; Inhibitors; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Mice; Mice, Knockout; Mice, Nude; Middle Aged; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Mutants; Mutation; Oncology; Pharmacology; Physiological aspects; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Ras genes; Signal Transduction - drug effects; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2941

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.