Premium
Resistance to vemurafenib resulting from a novel mutation in the BRAFV 600 E kinase domain
Author(s) -
Wagenaar Timothy R.,
Ma Leyuan,
Roscoe Benjamin,
Park Sung Mi,
Bolon Daniel N.,
Green Michael R.
Publication year - 2014
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12171
Subject(s) - vemurafenib , mutation , mutagenesis , protein kinase domain , drug resistance , mutant , cancer research , kinase , biology , melanoma , genetics , gene , metastatic melanoma
Summary Resistance to the BRAF inhibitor vemurafenib poses a significant problem for the treatment of BRAFV 600 E ‐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 BRAFV 600E. To search for possible mutations within BRAFV 600E 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 ( T 1514 A , encoding L 505 H ) that greatly increased drug resistance in cultured cells and mouse xenografts. The kinase activity of BRAFV 600 E / L 505 H was higher than that of BRAFV 600 E , resulting in cross‐resistance to a MEK inhibitor. However, BRAFV 600 E / L 505 H was less resistant to several other BRAF inhibitors whose binding sites were further from L 505 than that of PLX 4720. Our results identify a novel vemurafenib‐resistant mutant and provide insights into the treatment for melanomas bearing this mutation.