Therapeutics: Protein kinase B (AKT; AKT1; PKB; PKBA); BRAF; ES cell expressed Ras (ERAS)

In vitro studies suggest AKT inhibitors could help treat tumors with ERAS-driven resistance to BRAF inhibitors. In a mouse model of BRAF-mutant melanoma, insertional transposon mutagenesis identified ERAS mutations in tumors that relapsed after responding to a BRAF inhibitor but not in untreated controls. In BRAF-mutant melanoma cell lines, vector-induced overexpression of ERAS increased AKT phosphorylation and decreased responsiveness to BRAF inhibitor therapy compared with an empty vector. In the ERAS-overexpressing BRAF-mutant melanoma cells, an AKT inhibitor restored sensitivity to BRAF inhibitor therapy. Next steps could include validating the association between ERAS mutations and BRAF inhibitor resistance in patient samples.

Daiichi Sankyo Co. Ltd., Chugai Pharmaceutical Co. Ltd. and Roche market the BRAF inhibitor Zelboraf vemurafenib to treat melanoma...