Adaptive resistance to RAF inhibitors in melanoma.
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 ERK1/2 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.
Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA; Jefferson College of Graduate Studies, Thomas Jefferson University, Philadelphia, PA, USA.
Curtis H
CH
Kugel
Andrew E
AE
Aplin
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf
BRAF V600E; adaptive; dabrafenib; vemurafenib