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.
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We thank G. Mills, Y. Lu and N. Shih at the MD Anderson Reverse Phase Protein Array core facility; E. Fox at the Dana-Farber Cancer Institute Microarray core facility; S. Zhou for mouse husbandry; R. DePinho and G. Draetta and members of the laboratory, including S. Quayle, M. Chen, A. Blanchette and J. Kamara, for insightful discussions; R. Kwong for manuscript proofreading; D. Camacho for helping develop the TRAP algorithm; and M. Bar-Eli (University of Texas MD Anderson Cancer Center, Houston, Texas) for the SB-2 cell line. L.N.K. is supported by the Postdoctoral Fellowship (117842-PF-09-261-01-TBG) from the American Cancer Society. J.J.C. is supported by the US National Institutes of Health Director's Pioneer Award Program and the Howard Hughes Medical Institute. This work was supported by funding from the US National Institutes of Health to L.C. (U01 CA141508). L.C. is a recipient of the Abby S. and Howard P. Milstein 2009 Innovation Award for Melanoma and Skin Cancer Research and a CPRIT (Cancer Prevention Research Institute of Texas) Scholar in Cancer Research.
The authors declare no competing financial interests.
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Kwong, L., Costello, J., Liu, H. et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med 18, 1503–1510 (2012). https://doi.org/10.1038/nm.2941
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