Hubing Shi

TL;DR: It is shown that melanomas escape B-RAF(V600E) targeting not through secondary B-RF(V 600E) mutations but via receptor tyrosine kinase (RTK)-mediated activation of alternative survival pathway(s) or activated RAS-mediated reactivation of the MAPK pathway, suggesting additional therapeutic strategies.

TL;DR: The model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS–GTP too low to support RAF dimerization is supported and a novel mechanism of acquired resistance in patients is identified: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.

TL;DR: In this article, the authors identify the core resistance pathways and the extent of tumor heterogeneity during disease progression and show that mitogenactivated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common.

TL;DR: Alternative clinical strategies may potentially overcome distinct modes of ERK reactivation underlying acquired B-RAFi resistance in melanoma, which is sensitive to MEK1/2 inhibitor AZD6244/selumetinib or its combination with the B- RAFi vemurafenib.

TL;DR: High intra-tumoral cytolytic T cell inflammation prior to MAPKi therapy preceded CD8 T cell deficiency/exhaustion and loss of antigen presentation in half of disease-progressive melanomas, suggesting cross-resistance to salvage anti-PD-1/PD-L1 immunotherapy.