Advertisement

 

 

Concomitant BCORL1 and BRAF Mutations in Vemurafenib-Resistant Melanoma Cells.

Concomitant BCORL1 and BRAF Mutations in Vemurafenib-Resistant Melanoma Cells.
Author Information (click to view)

Mologni L, Costanza M, Sharma GG, Viltadi M, Massimino L, Citterio S, Purgante S, Raman H, Pirola A, Zucchetti M, Piazza R, Gambacorti-Passerini C,


Mologni L, Costanza M, Sharma GG, Viltadi M, Massimino L, Citterio S, Purgante S, Raman H, Pirola A, Zucchetti M, Piazza R, Gambacorti-Passerini C, (click to view)

Mologni L, Costanza M, Sharma GG, Viltadi M, Massimino L, Citterio S, Purgante S, Raman H, Pirola A, Zucchetti M, Piazza R, Gambacorti-Passerini C,

Advertisement

Neoplasia (New York, N.Y.) 2018 03 2820(5) 467-477 pii S1476-5586(17)30535-3
Abstract

BRAF is the most frequently mutated gene in melanoma. Constitutive activation of mutant BRAFleads to aberrant Ras-independent MAPK signaling and cell transformation. Inhibition of mutant BRAF is a current frontline therapy for such cases, with improved survival compared with chemotherapy. Unfortunately, reactivation of MAPK signaling by several mechanisms has been shown to cause drug resistance and disease recurrence. In this work, we describe the co-occurrence of an in-frame deletion within an amplified BRAFlocus and a missense point mutation of the transcriptional repressor BCORL1 in vemurafenib-resistant A375 melanoma cells. Functional data confirmed that truncated p47BRAFand mutant BCORL1both contribute to resistance. Interestingly, either endogenous BCORL1 silencing or ectopic BCORL1expression mimicked the effects of a CRISPR/Cas9-edited BCORL1locus, suggesting a complex mixture of loss- and gain-of-function effects caused by the mutation. Transcriptomic data confirmed this hypothesis. Finally, we show that the pan-RAF inhibitor sorafenib is not affected by expression of BRAF deletion variant and effectively synergizes with vemurafenib to block resistant cells, suggesting a possible intervention for this class of mutants.

Submit a Comment

Your email address will not be published. Required fields are marked *

fourteen − nine =

[ HIDE/SHOW ]