Inhibiting Drivers of Non-mutational Drug tolerance is a Salvage Strategy for Targeted Melanoma Therapy

這篇paper的重點在於找drug resistance early phase的機制。主要主張說MITF的上升是造成MAPK inhibitor抗藥性的原因，並且若能夠抑制MITF的濃度則將能恢復對MAPKi的sensitivity。並且用drug library screen FDA approved的藥物，主要找能夠抑制PAX3 和 MITF兩者的藥物，並發現nelfinavir能夠有如此效果。

而PAX3會正調控MITF的level，並且PAX3又受SKI/SMAD2 complex的負調控。而Nelfinavir可以增加SKI/SMAD2的量，進而去抑制PAX3-MITF axis，恢復melanoma cell對MAPKi 的sensivity。

MAPK inhibitor treatment will induce acquired resistance in melanoma

vemurafenib  = BRAFi

Dabrafenib = BRAFi

MITF = Microphthalmia-associated transcription factor

A375 cell line : melanoma cell line

AZD6244 : selumetinib, BRAFi

A375-GFP cell : already treated with BRAFi

疑問: long term treatment of BRAFi, 是否 MITF expression 都是elevated的?

         if so, in that case, would MITF inhbition still decrease resistance?

use a FDA drug library to screen for drugs that target both PAX3 and MITF

Z score of -5 and >90% cell viability are setted for screening criteria

mutant NRAS is found in ~18% of melanomas with acquired resistance