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Adaptive resistance to RAF inhibitors in melanoma
Author(s) -
Kugel Curtis H.,
Aplin Andrew E.
Publication year - 2014
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12264
Subject(s) - dabrafenib , vemurafenib , trametinib , melanoma , medicine , acquired resistance , cancer research , targeted therapy , mek inhibitor , disease , oncology , metastatic melanoma , cancer , mapk/erk pathway , signal transduction , biology , genetics
Summary The discovery of activating mutations in BRAF at high frequency in cutaneous melanoma opened the door to new treatment options, which have resulted in significantly better patient outcomes. Treatments such as the FDA ‐approved RAF inhibitor vemurafenib and the more recently approved dabrafenib and trametinib combination therapy are designed to target the ERK 1/2 pathway. Initial success in targeting this pathway is evidenced by the high percentage of melanoma patients who undergo tumor remission. However, the beneficial effects of these targeted therapies are usually short‐lived due to the development of resistance, which leads to disease progression. As a result, studies have focused on the acquired forms of resistance that develop following continued exposure to therapy. Conversely, far fewer studies have investigated the adaptive forms of resistance, which activate rapidly, promote cell survival, and may underlie the development of acquired resistance by providing melanoma cells the time to develop additional mutations. We provide a detailed review of the known mechanisms of adaptive resistance in melanoma and relate them to similar responses to targeted therapies in other tumor types.