Fig. 6.
(A) Proposed mechanism of pathway hyperactivation in lung cancer. Intermediate driver mutants cooperate with previously established driver mutants such as BRAF and KRAS to further activate the MAPK proproliferative pathway. FGFR4P712T mediates pathway activation upstream of KRAS and possibly via additional intermediate substrates other than RAFs, PAK5T538N mediates activation at the RAF level, and MAP3K9E179K acts as a direct MEK kinase. (B) Four NSCLC cell lines (H2009, H2087, H2122 harboring MEK/ERK activating mutants, and H2126 with no identifiable MEK/ERK activating mutant) were treated with the MEK inhibitor AZD6244 at 3 µM, and cytotoxicity was determined by MTT assay. Data (n = 9) were normalized to untreated cells (UNT; DMSO, <0.01%). Error bars show SD. P values were calculated by using one-tailed paired Student t test (*P < 0.05 vs. untreated control).