Abstract
BackgroundGain of function mutations in B-RAF and N-RAS occur frequently in melanoma, leading to mitogen activating protein kinase (MAPK) pathway activation, and this pathway is the target of drugs in development. Our purpose was to study clinical characteristics of patients with mutations in this pathway and to determine activity of inhibitors of B-RAF and MEK in short term cultures grown from tumors of some of these patients.MethodsClinical and pathologic data were collected retrospectively on melanoma patients tested for B-RAF and N-RAS mutations at the Yale Cancer Center and associations with survival were determined. We studied in vitro activity of the pan-RAF inhibitor, RAF265, and the MEK inhibitor, MEK162, in 22 melanoma short term cultures. We further characterized the effect of MEK inhibition on apoptosis and growth of melanoma cultures.ResultsIn a cohort of 144 metastatic melanoma patients we found that patients with N-RAS mutant melanoma had a worse prognosis. These patients were more likely to have brain metastases at the time of presentation with metastatic disease than their N-RAS-wild-type counterparts. All N-RAS mutant melanoma cultures tested in our study (n = 7) were sensitive to MEK inhibition162. Exposure to MEK162 reduced ERK1/2 phosphorylation, and induced apoptosis. Clonogenic survival was significantly reduced in sensitive melanoma cell cultures.ConclusionsThe prognosis of patients with melanoma expressing constitutively active N-RAS is poor, consistent with studies performed at other institutions. N-RAS mutant melanoma cultures appear to be particularly sensitive to MEK162, supporting ongoing clinical trials with MEK162 in N-RAS mutated melanoma.
Highlights
Gain of function mutations in B-RAF and N-RAS occur frequently in melanoma, leading to mitogen activating protein kinase (MAPK) pathway activation, and this pathway is the target of drugs in development
Patients with N-RAS and B-RAF mutations have a higher incidence of CNS metastasis at the time of diagnosis of stage IV disease compared to patients who are wildtype for B-RAF and N-RAS, and N-RAS mutation status was identified as an independent predictor of shorter survival after a diagnosis of stage IV melanoma [9]
Mutations were found in B-RAF in 43.7%, N-RAS in 27.7%, and 28.4% were wild type (WT) for both
Summary
Gain of function mutations in B-RAF and N-RAS occur frequently in melanoma, leading to mitogen activating protein kinase (MAPK) pathway activation, and this pathway is the target of drugs in development. Prior to the recent advances in therapy for patients with stage IV disease, the prognosis of metastatic melanoma was very poor with a median survival of less than 12 months [1]. One of the most significant advances in recent years was the elucidation of the etiological role of the mitogen activated protein kinase (MAPK) pathway in melanomagenesis, the roles of mutant B-RAF and N-RAS [2]. Several recent studies have examined the associations between B-RAF and N-RAS mutations and clinical characteristics and prognosis in patients with metastatic melanoma [4,7,8]. Patients with N-RAS and B-RAF mutations have a higher incidence of CNS (central nervous system) metastasis at the time of diagnosis of stage IV disease compared to patients who are wildtype for B-RAF and N-RAS, and N-RAS mutation status was identified as an independent predictor of shorter survival after a diagnosis of stage IV melanoma [9]
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