Network Analysis of NRAS Activity Defines a Synergistic Drug Strategy

NRAS mutations are common in melanoma, leading to enhanced downstream activation of the MAPK cascade. However, the use of MEK inhibitors alone has limited efficacy in these tumors, and attempts to directly target oncogenic RAS activity have thus far been unsuccessful. To establish improved drug combinations that mimic RAS inhibition, Kwong and colleagues used an inducible genetically engineered mouse model, in which melanoma formation is dependent on sustained mutant NRAS^Q61K expression, to analyze the effects of perturbations on the oncogenic NRAS signaling network. In contrast with withdrawal of mutant NRAS expression, which resulted in tumor regression, treatment with pharmacologic MEK inhibitors was only sufficient to induce tumor stasis, suggesting that these drugs do not completely block NRAS-dependent signaling. Consistent with this idea, RAS inhibition via elimination of NRAS^Q61K expression triggered apoptosis and diminished mitotic activity in mutant NRAS-driven tumors, whereas MEK inhibition only induced apoptosis, indicating that cell-cycle arrest is also required for tumor regression. Further-more, comparison of global expression profiles and knowledge-based pathway analysis showed an enrichment of cell-cycle regulatory pathways, including activation of the Rb checkpoint, upon NRAS^Q61K withdrawal. Network modeling of gene–pathway transcriptional relationships identified cyclin-dependent kinase 4 (CDK4) as a critical mediator of this cell-cycle checkpoint, suggesting that CDK4 inhibition may be clinically beneficial. Indeed, CDK4 blockade synergized with a MEK inhibitor to promote both cell-cycle arrest and apoptosis and to induce tumor regression in mouse and human xenograft models. In addition, partial inhibition of NRAS–MAPK signaling at an earlier time point after NRAS^Q61K withdrawal stimulated apoptosis but not cell-cycle arrest, supporting a gradient model of NRAS signaling in which biologic outputs are gated at distinct thresholds. These findings underscore the usefulness of systems biology approaches for developing nonobvious combinatorial therapeutic strategies.

Kwong LN, Costello JC, Liu H, Jiang S, Helms TL, Langsdorf AE, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med 2012;18:1503–10.

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