Maximizing The Efficacy Of Mapk-Targeted Treatment In Ptenlof/Braf(Mut) Melanoma Through Pi3k And Igf1r Inhibition

The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of BRAF-mutant (BRAF(MUT)) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling network. Concomitant PTEN loss of function (PTENLOF) occurs in approximately 40% of BRAF(MUT) melanomas. In this study, we sought to identify the nodes of the PTEN/PI3K pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of PTENLOF/BRAF(MUT) melanoma. Large-scale compound sensitivity profiling revealed that PTENLOF melanoma cell lines were sensitive to PI3K beta inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3K beta inhibitor identified an adaptive response involving the IGF1R-PI3K alpha axis. Combined inhibition of the MAPK pathway, PI3K beta, and PI3K alpha or insulin-like growth factor receptor 1 (IGF1R) synergistically sustained pathway blockade, induced apoptosis, and inhibited tumor growth in PTENLOF/BRAF(MUT) melanoma models. Notably, combined treatment with the IGF1R inhibitor, but not the PI3K alpha inhibitor, failed to elevate glucose or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3K beta + IGF1R, and MAPK pathway inhibitors in PTENLOF/BRAF(MUT) melanoma patients to achieve maximal response. (C) 2015 AACR.