Antoni Ribas, MD
Department of Medicine, Division of Hematology-Oncology; Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA), Los Angeles, CA;
The histology of melanoma is dependent upon driver oncogenic mutations in a major signaling pathway, with up to 70% of advanced melanomas having mutually exclusive activating mutations in the mitogen-activated protein kinase (MAPK) pathway. Mutations closely follow different clinical-pathological presentations of melanoma. The BRAFV600E
mutation makes up over 90% of the mutations in BRAF
, which are present in approximately 50% of all melanomas. The BRAF inhibitor vemurafenib induces high antitumor activity in patients with BRAF
-mutant metastatic melanoma and improvement in survival, leading to its approval by the FDA. Similar results have been eported with another BRAF inhibitor, dabrafenib. Resistance to BRAF inhibitors does not follow the common pathways of resistance to other ATP-competitive targeted kinase inhibitors. Instead, so far, mechanisms of resistance can be divided into two major groups: reactivation of the MAPK pathway and MAPK-independent pathways. An understanding of acquired resistance to BRAF inhibitors is already resulting in new combination therapies to prevent or treat some of the resistance mechanisms, and additional novel combinations are under study.
Biology of MAPK and BRAF Mutations in Melanoma
Melanoma has become one of the best examples of a cancer histology dependent upon driver oncogenic mutations in a major signaling pathway. This is because up to 70% of advanced melanomas have mutually exclusive activating mutations in the mitogen-activated protein kinase (MAPK) pathway, resulting in constitutive signaling leading to oncogenic cell proliferation and escape from apoptosis.1
These mutations are not randomly distributed since they closely follow different presentations of melanoma:
Mutations in c-Kit: Mutations in the c-Kit receptor tyrosine kinase (RTK) are located in similar exons as in gastrointestinal stromal tumors (GISTs) and are more prevalent in mucosal melanomas and acral lentiginous melanomas.2 These are two subtypes of melanoma that are not related to the carcinogenic effects of ultraviolet light or history of sunburns. Overall, c-Kit mutations are present in less than 2% of melanomas.
Mutations in NRAS: RAS mutations in melanoma are preferentially in NRAS, as opposed to other cancers where mutations are more frequent in KRAS or HRAS. They cluster in the RAS hotspot mutation sites, in particular at Q61, and were the first oncogenic driver mutation described in melanomas.3 These mutations tend to appear in melanomas located on intermittently sun-exposed or chronically sunexposed skin. Emergent data suggest that they are more frequent in melanomas in older individuals. Overall, NRAS mutations are present in approximately 20% of melanomas.
Mutations in BRAF: The BRAFV600E mutation, which leads to the substitution of valine by glutamic acid at position 600 (V600E) in the BRAF kinase, is the most common point mutation in melanoma, present in approximately 50% of cases.4,5 The BRAFV600E mutation makes up over 90% of the mutations in BRAF, with other amino acid substitutions at this position (V600K, V600D, or V600R) being much less frequent.5 Increasing evidence suggests that the frequency of the BRAFV600E mutation is inversely correlated with age, with a higher incidence in patients between ages 20 to 40 years than patients older than age 60 years.