PI3′-Kinase Inhibition Forestalls the Onset of MEK1/2 Inhibitor Resistance in BRAF-Mutated Melanoma
PI3′-Kinase Inhibition Forestalls the Onset of MEK1/2 Inhibitor Resistance in BRAF-Mutated Melanoma
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DOI：
10.1158/2159-8290.cd-14-0856
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发表时间：
2015-02-01
期刊：
影响因子：
28.2
通讯作者：
McMahon, Martin
中科院分区：
文献类型：
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作者：
Deuker, Marian M.;Durban, Victoria Marsh;McMahon, Martin
磷脂酰肌醇3‘(PI3’)-脂信号与致癌的BRAF(V600E)协同促进黑色素瘤的发生。持续的PI3‘-脂质产生通常是通过沉默PI3’-脂磷酸酶PTEN，或较少通过编码PI3‘-激酶-α(PI3Kα)催化亚基110 kDa的PIK3CA的突变激活来实现的。为了确定BRAF突变的黑色素瘤对PI3K催化异构体的依赖性，我们结合黑色素瘤来源的细胞系和基因工程小鼠(GEM)模型，使用了药理学的、异构体选择性的PI3K抑制剂。尽管BRAF(V600E)/PIK3CA(H1047R)黑色素瘤对选择性PI3Kα阻断的抗增殖作用敏感，但抑制BRAF(V600E)/PTEN阴性黑色素瘤的增殖需要联合阻断PI3Kα、PI3K Delta和PI3K Gamma，而对PI3Kβ阻断不敏感。在GEM模型中，异构体选择性PI3K抑制产生细胞抑制效应，但显著促进BRAF(V600E)通路靶向抑制反应的黑色素瘤消退。有趣的是，在两个独立的BRAF(V600E)驱动的GEM黑色素瘤模型中，PI3K抑制预防了MEK抑制剂耐药的发生。这些结果表明，与PI3K抑制剂联合治疗可能是延长BRAF突变黑色素瘤患者对BRAF(V600E)通路靶向治疗的临床反应持续时间的有用策略。在这里，我们表明，联合治疗PI3K抑制剂显著预防了BRAF突变的GEM黑色素瘤模型中MEK1/2抑制剂耐药疾病的发生。这些结果为联合应用BRAF(V600E)和PI3K通路靶向抑制剂治疗部分BRAF突变黑色素瘤患者提供了一个概念性框架。(C)2014年AACR。
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-alpha (PI3K alpha). 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 PI3K alpha blockade, inhibition of BRAF(V600E)/PTENNull melanoma proliferation required combined blockade of PI3K alpha, PI3K delta, and PI3K gamma, and was insensitive to PI3K beta 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. (C) 2014 AACR.