Abstract:
:BRAF is the most frequently mutated gene in melanoma. Constitutive activation of mutant BRAFV600E leads 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 BRAFV600E locus and a missense point mutation of the transcriptional repressor BCORL1 in vemurafenib-resistant A375 melanoma cells. Functional data confirmed that truncated p47BRAFV600E and mutant BCORL1Q1076H both contribute to resistance. Interestingly, either endogenous BCORL1 silencing or ectopic BCORL1Q1076H expression mimicked the effects of a CRISPR/Cas9-edited BCORL1Q1076H locus, 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.
journal_name
Neoplasiajournal_title
Neoplasia (New York, N.Y.)authors
Mologni L,Costanza M,Sharma GG,Viltadi M,Massimino L,Citterio S,Purgante S,Raman H,Pirola A,Zucchetti M,Piazza R,Gambacorti-Passerini Cdoi
10.1016/j.neo.2018.02.009subject
Has Abstractpub_date
2018-05-01 00:00:00pages
467-477issue
5eissn
1522-8002issn
1476-5586pii
S1476-5586(17)30535-3journal_volume
20pub_type
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