PI3'-kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAF-mutated melanoma.

UNLABELLED: Phosphatidylinositide 3' (PI3')-lipid signaling cooperates with oncogenic BRAF(V600E) to promote melanomagenesis. Sustained PI3'-lipid production commonly occurs via silencing of the PI3'-lipid phosphatase PTEN or, less commonly, through mutational activation of PIK3CA, encoding the 110-kDa catalytic subunit of PI3'-kinase-α (PI3Kα). To define the PI3K catalytic isoform dependency of BRAF-mutated melanoma, we used pharmacologic, isoform-selective PI3K inhibitors in conjunction with melanoma-derived cell lines and genetically engineered mouse (GEM) models. Although BRAF(V600E)/PIK3CA(H1047R) melanomas were sensitive to the antiproliferative effects of selective PI3Kα blockade, inhibition of BRAF(V600E)/PTEN(Null) melanoma proliferation required combined blockade of PI3Kα, PI3Kδ, and PI3Kγ, and was insensitive to PI3Kβ blockade. In GEM models, isoform-selective PI3K inhibition elicited cytostatic effects, but significantly potentiated melanoma regression in response to BRAF(V600E) pathway-targeted inhibition. Interestingly, PI3K inhibition forestalled the onset of MEK inhibitor resistance in two independent GEM models of BRAF(V600E)-driven melanoma. These results suggest that combination therapy with PI3K inhibitors may be a useful strategy to extend the duration of clinical response of patients with BRAF-mutated melanoma to BRAF(V600E) pathway-targeted therapies. SIGNIFICANCE: Although BRAF(V600E) pathway-targeted therapies elicit melanoma regression, the onset of drug resistance limits the durability of response. Here, we show that combined treatment with PI3K inhibitors significantly forestalled the onset of MEK1/2 inhibitor-resistant disease in BRAF-mutated GEM melanoma models. These results provide a conceptual framework for the combined deployment of BRAF(V600E) plus PI3K pathway-targeted inhibitors in the treatment of a subset of patients with BRAF-mutated melanoma. ©2014 American Association for Cancer Research.