UNASSIGNED: The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of @entity817 -mutant ( @entity2189 ) @entity320 . However, even @entity817 / @entity8047 inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling network. Concomitant @entity983 loss of function ( @entity983 ) occurs in approximately 40% of @entity817 ( @entity2189 ) @entity320 . In this study, we sought to identify the nodes of the @entity983 / @entity10412 pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of @entity983 ( @entity983 )/ @entity817 ( @entity2189 ) @entity320 . Large-scale compound sensitivity profiling revealed that @entity983 ( @entity983 ) @entity320 cell lines were sensitive to PI3Kb inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3Kb inhibitor identified an adaptive response involving the @entity2856 -PI3Ka axis. Combined inhibition of the MAPK pathway, PI3Kb, and PI3Ka or insulin-like growth factor receptor 1 ( @entity2856 ) synergistically sustained pathway blockade, induced apoptosis, and inhibited @entity5 growth in @entity983 ( @entity983 )/ @entity817 ( @entity2189 ) @entity320 models. Notably, combined treatment with the @entity2856 inhibitor, but not the PI3Ka inhibitor, failed to elevate @entity413 or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3Kb + @entity2856 , and MAPK pathway inhibitors in @entity983 ( @entity983 )/ @entity817 ( @entity2189 ) @entity320 @entity1 to achieve maximal response. @entity5 Res; 76(2); 390-402.   2015 AACR.

Maximizing the Efficacy of MAPK-Targeted Treatment in PTENLOF/BRAFMUT Melanoma through XXXX and @entity2856 Inhibition.

@entity1 :: ('9606', 'Species') :: ['patients'] @entity8047 :: ('5609', 'Gene') :: ['MEK'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'Cancer'] @entity2856 :: ('3480', 'Gene') :: ['IGF1R'] @entity2189 :: ('4594', 'Gene') :: ['BRAF(MUT)', 'MUT'] @entity10412 :: ('5293', 'Gene') :: ['PI3K'] @entity983 :: ('5728', 'Gene') :: ['PTEN(LOF)', 'PTEN', 'LOF'] @entity413 :: ('MESH:D005947', 'Chemical') :: ['glucose'] @entity817 :: ('673', 'Gene') :: ['BRAF'] @entity320 :: ('MESH:D008545', 'Disease') :: ['melanoma', 'melanomas']
@entity10412 :: (5293,Gene) :: ['PI3K']
