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Targeting hyperactive MAPK signaling has proven to be an effective treatment for a variety of different cancers. Responses to the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitors trametinib and cobimetinib are, however, transient, and complete remission is rarely observed; rather, outgrowth of resistant clones within progressed tumors appears inevitable. These resistant tumors display great heterogeneity, which poses a major challenge to any salvage therapy. Recent focus has, therefore, been on the early dynamics of inhibitor response during tumor regression. During this time, cells can persist in an adapted tolerant state, which results in a phase of nonmutational drug tolerance. In this article, we discuss how inhibition of the MAPK pathway leads to an adaptive rewiring that evolves from the relief of immediate negative feedback loops to short-term gene expression changes and adaptation of intracellular signaling. Tolerance can also be mediated by external signaling from the tumor microenvironment, which itself adapts upon treatment and the selection for cells with an innate drug-tolerant phenotype. In preclinical models, combination treatment with receptor tyrosine kinase (RTK) inhibitors (lapatinib and dasatinib), histone deacetylase (HDAC) inhibitors (vorinostat and entinostat), or drugs targeting cancer-specific mechanisms (nelfinavir in melanoma) can overcome this early tolerance. A better understanding of how nonmutational tolerance is created and supported may hold the key to better combinational strategies that maintain drug sensitivity. Clin Cancer Res; 22(24); 5966-70. ©2016 AACR.

Molecular Pathways: Maintaining MAPK Inhibitor Sensitivity by Targeting Nonmutational Tolerance