Abstract：
: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 (PTEN(LOF)) 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 PTEN(LOF)/BRAF(MUT) melanoma. Large-scale compound sensitivity profiling revealed that PTEN(LOF) melanoma cell lines were sensitive to PI3Kβ inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3Kβ inhibitor identified an adaptive response involving the IGF1R-PI3Kα axis. Combined inhibition of the MAPK pathway, PI3Kβ, and PI3Kα or insulin-like growth factor receptor 1 (IGF1R) synergistically sustained pathway blockade, induced apoptosis, and inhibited tumor growth in PTEN(LOF)/BRAF(MUT) melanoma models. Notably, combined treatment with the IGF1R inhibitor, but not the PI3Kα inhibitor, failed to elevate glucose or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3Kβ + IGF1R, and MAPK pathway inhibitors in PTEN(LOF)/BRAF(MUT) melanoma patients to achieve maximal response.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Herkert B,Kauffmann A,Mollé S,Schnell C,Ferrat T,Voshol H,Juengert J,Erasimus H,Marszalek G,Kazic-Legueux M,Billy E,Ruddy D,Stump M,Guthy D,Ristov M,Calkins K,Maira SM,Sellers WR,Hofmann F,Hall MN,Brachmann SMdoi
10.1158/0008-5472.CAN-14-3358subject
Has Abstractpub_date
2016-01-15 00:00:00pages
390-402issue
2eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-14-3358journal_volume
76pub_type
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