The early resistance to BARF(V600)-mutant melanoma is triggered by reactivation of MAPK pathway

 

For treating BRAF(V600)-mutant metastatic melanoma, the combination of BRAF and MEK inhibitor, that targets mitogen-activated protein kinase (MAPK) signaling, is proved to be effective in clinical trials. However, drug resistance remains a barrier for a better therapeutic efficiency. In regards to mechanism of emerging drug resistance, Long et al. demonstrated MAPK pathway was reactivated in early stage of resistance to combination therapy. The article was published on Nature Communication, recently.

 

The study involved 10 BRAF(V600)-mutant melanoma patients, and totally 20 melanoma samples. Patients were treated with the combination of dabrafenib and trametinib, which are the inhibitors of BRAF and MEK, respectively. 11 out of 20 tumors were identified progressing, and within progressing tumors, 9/11 preformed drug resistance. Moreover, MAPK reactivation were found in 9/10 tumors. Although the resistance to BRAF inhibitor monotherapy is also triggered by MAPK reactivation, the combination therapy has different mechanism. Researchers proved the primary reactivation of MAPK was mediated by BRAK amplification and mutations in NRAS and MEK2C^125S. The findings indicates the higher efficiency of signaling inhibitor may require the combination inhibition of multiple pathways related to cell proliferation and survival.

 

Reference:
Nat Commun. 2014 Dec 2;5:5694.

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S2673	Trametinib (GSK1120212)	Trametinib (GSK1120212, JTP-74057) is a highly specific and potent MEK1/2 inhibitor with IC50 of 0.92 nM/1.8 nM in cell-free assays, no inhibition of the kinase activities of c-Raf, B-Raf, ERK1/2. Trametinib activates autophagy and induces apoptosis.

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