Trametinib for patients with advanced melanoma

Abstract

Gerald Falchook and colleagues show clinical activity of the MEK inhibitor trametinib in patients with either BRAF-mutant or wild-type melanoma. Recently, two essential topics for melanoma have been reported: hepatocyte growth factor (HGF)-dependent resistance to therapy and new driver mutations in melanoma. Stroma-mediated resistance to treatment of BRAF-mutant melanoma is common and HGF secretion from stromal cells seems to be responsible for this drug resistance. Analysis of biopsy samples from patients with BRAF-mutant melanoma suggests that patients with abundant HGF from stromal cells have poor responses to treatment. Furthermore, an inverse relation has been reported between plasma HGF concentration and response to treatment in patients with BRAF-mutant melanoma. HGF secretion leads to activation of the HGF receptor MET, and dual inhibition of RAF and either HGF or MET results in reversal of drug resistance in BRAFmutant melanoma. In Falchook and colleagues’ study, examination by immuno histochemistry of whether HGF expression in melanoma sections correlated with poor responses to the MEK inhibitor trametinib would have been informative, not only in patients with the BRAF mutation, but also in patients with wild-type BRAF. These results would clarify the possibility that a combination of the MEK inhibitor and MET inhibitors have a synergistic eff ect. Moreover, although EGF is less able than HGF to reactivate ERK in most melanoma cell lines, EGF and EGFR mediated resistance might be of interest in melanoma and in colon cancers. For driver mutations, six genes related to melanoma have been newly identifi ed (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2), with RAC1 mutations also reported. The Illumina platform was used in Falchook and colleagues’ study to analyse the mutational and copy number status of 78 diff erent genes commonly implicated in tumorigenesis. Within these data, is there any information about the six new melanoma genes? If these driver mutations are present, examination of whether they correlate with reduced responses to therapy with trametinib would be interesting, because such examination would not only contribute to drug response predictions but also might help select other treatment options, including combination therapies. Furthermore, data on amplifi cation of BRAF, either with or without mutations, could provide information on whether copy number of this gene plays a role in response to therapy? In the context of treatment with the MEK inhibitor trametinib, an integrated examination including HGF secretion and other gene mutations would open up the possibility of prediction of drug response and combination therapy.