BACKGROUND: @entity12363 mutations in @entity320 can confer resistance to @entity817 inhibitors, although preexisting @entity12363 (P124) mutations do not preclude clinical responses. We sought to determine whether recurrent, preexisting @entity12363 (P124) mutations affected clinical outcome in @entity817 inhibitor-treated @entity1 with @entity320 . METHODS: Data from four published datasets were analyzed to determine whether preexisting @entity12363 (P124) mutations affect radiologic response or progression-free survival (PFS) in @entity1 with @entity817 (V600)-mutant metastatic @entity320 treated with @entity5457 or @entity5458 . The effects of @entity12363 (P124) mutations on MAPK pathway activity and response to @entity817 inhibition were also investigated in a series of cell models. RESULTS: In a pooled analysis of 123 @entity1 , the presence of a pretreatment @entity12363 (P124) mutation (N = 12, 10%) was associated with a poorer RECIST response (33% vs. 72% in @entity12363 ( @entity68390 /S) vs. @entity12363 ) wild-type, P = 0.018), and a shorter PFS (median 3.1 vs. 4.8 months, P = 0.004). Furthermore, @entity12363 ( @entity68390 /S) mutations were shown to have independent kinase activity and introduction of these mutations into a @entity817 -mutant @entity320 cell line diminished inhibition of @entity3963 phosphorylation by @entity5458 and enhanced clonogenic survival in the presence of @entity5458 compared with cells ectopically expressing wild-type @entity12363 . Consistent with these data, two @entity817 -mutant cell lines with endogenous @entity12363 (P124) mutations showed intermediate sensitivity to @entity5458 , but were highly sensitive to downstream inhibition of @entity8047 or @entity3963 . CONCLUSION: Taken together, our data indicate that preexisting @entity12363 (P124) mutations are associated with a reduced response to @entity817 inhibitor therapy and identify a subset of @entity1 with @entity817 -mutant @entity320 likely to benefit from combination therapies involving @entity8047 or @entity3963 inhibitors. Clin Cancer Res; 1-8.   2014 AACR.

Preexisting MEK1P124 Mutations Diminish Response to XXXX Inhibitors in @entity320 @entity1 .

@entity1 :: ('9606', 'Species') :: ['patients'] @entity8047 :: ('5609', 'Gene') :: ['MEK'] @entity3963 :: ('5594', 'Gene') :: ['ERK'] @entity68390 :: ('p|SUB|P|124|Q', 'ProteinMutation') :: ['P124Q'] @entity5458 :: ('MESH:C561627', 'Chemical') :: ['dabrafenib'] @entity817 :: ('673', 'Gene') :: ['BRAF'] @entity320 :: ('MESH:D008545', 'Disease') :: ['melanoma'] @entity5457 :: ('MESH:C551177', 'Chemical') :: ['vemurafenib'] @entity12363 :: ('5604', 'Gene') :: ['MEK1', 'MEK1(P124']
@entity817 :: (673,Gene) :: ['BRAF']
