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Tumor adaptation and resistance to RAF inhibitors

Nature Medicine volume 19, pages 1401–1409 (2013)Cite this article

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Abstract

RAF kinase inhibitors have substantial therapeutic effects in patients with BRAF-mutant melanoma. However, only rarely do tumors regress completely, and the therapeutic effects are often temporary. Several mechanisms of resistance to RAF inhibitors have been proposed. The majority of these cause ERK signaling to become insensitive to treatment with RAF inhibitors by increasing the amount of RAF dimers in cells, whereas others bypass the dependence of the tumor on mutant RAF. One motivation for studying mechanisms of drug resistance is that such efforts may suggest new therapeutic targets or rational combination strategies that delay or prevent the emergence of drug-resistant clones. Here, we review the current model of RAF inhibitor resistance with a focus on the implications of this model on ongoing laboratory and clinical efforts to develop more effective therapeutic strategies for patients with BRAF-mutant tumors.

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Figure 1: ERK signaling under physiologic conditions and in tumors harboring BRAF V600E mutations.

Neil Smith

Figure 2: RAF inhibitor resistance mechanisms that result in reactivated ERK signaling in the presence of drug.

Neil Smith

Figure 3: Adaptation to RAF inhibitors in tumors harboring BRAF V600E mutations.

Neil Smith

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  1. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Piro Lito, Neal Rosen & David B Solit

  2. Program in Molecular Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Piro Lito & Neal Rosen

  3. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    David B Solit

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Lito, P., Rosen, N. & Solit, D. Tumor adaptation and resistance to RAF inhibitors. Nat Med 19, 1401–1409 (2013). https://doi.org/10.1038/nm.3392

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