title: PI3'-kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAF-mutated melanoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center and Department of Cell and Molecular Pharmacology, University of California, San Francisco, San Francisco, California.
authors.forename: Marian M
authors.initials: MM
authors.lastname: Deuker
authors.affiliation: Helen Diller Family Comprehensive Cancer Center and Department of Cell and Molecular Pharmacology, University of California, San Francisco, San Francisco, California.
authors.forename: Victoria
authors.initials: V
authors.lastname: Marsh Durban
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
authors.affiliation: Helen Diller Family Comprehensive Cancer Center and Department of Cell and Molecular Pharmacology, University of California, San Francisco, San Francisco, California. mcmahon@cc.ucsf.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
mesh_terms: D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D011897:Random Allocation; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D002219:Carbamates; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013844:Thiazoles; C585539:Alpelisib; C000601108:encorafenib; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D051059:PTEN Phosphohydrolase