Two states of BRAFV600 mutant melanoma that related to MAPK inhibition resistance

 

Melanoma is a kind of serious skin cancer develops from melanocytes, cells produce melanin. BRAF^V600 mutations are occurred in most of melanomas, and activate MEK and ERK signaling of mitogen activated protein kinase (MAPK) pathway. Despite the considerable effect of MAPK inhibitor on the control of BRAF^V600 mutant melanoma, 10-20% of patients show innate or intrinsic resistance to the therapy. Konieczkowski et al. revealed the mechanism of MAPK inhibition on BRAF^V600 mutant melanomas. The article was published on Cancer Discovery.

 

Researchers showed two distinct transcriptional states of BRAF^V600 mutant melanoma: one has high expression level and transcriptional activity of MITF and is sensitive to MAPK inhibitor, compared with another one, which has low expression level and activity of MITF and specifically resist to MAPK inhibitor. They found the two different states in melanocytes are mediated by the balance of aberrant MAPK signaling activation and MITF activity, result in the MITF-low/NF-κB-high state and MITF-high/NF-κB-low state, respectively. In addition, the aberrant expression of MITF impairs induction of the NF-κB-high state, indicating the two states in melanocytes are also related to dysregulation of MITF. The findings can facilitate the study of new therapeutic strategies against the drug resistance to MAPK pathway inhibitors.

 

Reference:
Cancer Discov. 2014 Jul;4(7):816-27.

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MEK c-Met TAM receptors (Tyro-3,Axl,and Mertk) Raf VEGFR