Title

Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain

UMMS Affiliation

Programs in Gene Function and Expression and Molecular Medicine; Department of Biochemistry and Molecular Pharmacology

Date

1-2014

Document Type

Article

Disciplines

Cancer Biology | Cell Biology | Genetics and Genomics

Abstract

Resistance to the BRAF inhibitor vemurafenib poses a significant problem for the treatment of BRAFV600E-positive melanomas. It is therefore critical to prospectively identify all vemurafenib resistance mechanisms prior to their emergence in the clinic. The vemurafenib resistance mechanisms described to date do not result from secondary mutations within BRAFV600E. To search for possible mutations within BRAFV600E that can confer drug resistance, we developed a systematic experimental approach involving targeted saturation mutagenesis, selection of drug-resistant variants, and deep sequencing. We identified a single nucleotide substitution (T1514A, encoding L505H) that greatly increased drug resistance in cultured cells and mouse xenografts. The kinase activity of BRAFV600E/L505H was higher than that of BRAFV600E, resulting in cross-resistance to a MEK inhibitor. However, BRAFV600E/L505H was less resistant to several other BRAF inhibitors whose binding sites were further from L505 than that of PLX4720. Our results identify a novel vemurafenib-resistant mutant and provide insights into the treatment for melanomas bearing this mutation.

Rights and Permissions

Citation: Wagenaar TR, Ma L, Roscoe B, Park SM, Bolon DN, Green MR. Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain. Pigment Cell Melanoma Res. 2014 Jan;27(1):124-33. doi: 10.1111/pcmr.12171. Link to article on publisher's website

Comments

Co- author Benjamin Roscoe is a doctoral student in the Biochemistry and Molecular Pharmacology program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

Related Resources

Link to article in PubMed

Keywords

BRAFV600E, Deep sequencing, Drug resistance, Saturation mutagenesis, Vemurafenib

PubMed ID

24112705