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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. BRAFV600 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 BRAFV600 mutant melanoma, 10-20% of patients show innate or intrinsic resistance to the therapy. Konieczkowski et al. revealed the mechanism of MAPK inhibition on BRAFV600 mutant melanomas. The article was published on Cancer Discovery.

 

Researchers showed two distinct transcriptional states of BRAFV600 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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S1152 PLX-4720 PLX4720 is a potent and selective inhibitor of B-RafV600E with IC50 of 13 nM in a cell-free assay, equally potent to c-Raf-1(Y340D and Y341D mutations), 10-fold selectivity for B-RafV600E than wild-type B-Raf.
S1008 Selumetinib (AZD6244) Selumetinib (AZD6244, ARRY-142886) is a potent, highly selective MEK inhibitor with IC50 of 14 nM for MEK1 and Kd value of 530 nM for MEK2. It also inhibits ERK1/2 phosphorylation with IC50 of 10 nM, no inhibition to p38α, MKK6, EGFR, ErbB2, ERK2, B-Raf, etc. Selumetinib suppresses cell proliferation, migration and trigger apoptosis. Phase 3.
S4001 Cabozantinib malate Cabozantinib malate (XL184) is the malate of Cabozantinib, a potent VEGFR2 inhibitor with IC50 of 0.035 nM and also inhibits c-Met, Ret (c-Ret), Kit (c-Kit), Flt-1/3/4, Tie2, and AXL with IC50 of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM in cell-free assays, respectively. Cabozantinib malate (XL184) induces apoptosis.
S1111 Foretinib Foretinib is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met (c-Met) and KDR with IC50 of 0.4 nM and 0.9 nM in cell-free assays. Less potent against Ron, Flt-1/3/4, Kit (c-Kit), PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

Related Targets

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