Data from Maximizing the Efficacy of MAPK-Targeted Treatment in <i>PTEN</i>^LOF<i>/BRAF</i>^MUT Melanoma through PI3K and IGF1R Inhibition

Abstract

&lt;div&gt;Abstract&lt;p&gt;The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of &lt;i&gt;BRAF&lt;/i&gt;-mutant (&lt;i&gt;BRAF&lt;/i&gt;&lt;sup&gt;MUT&lt;/sup&gt;) 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 &lt;i&gt;PTEN&lt;/i&gt; loss of function (&lt;i&gt;PTEN&lt;/i&gt;&lt;sup&gt;LOF&lt;/sup&gt;) occurs in approximately 40% of &lt;i&gt;BRAF&lt;/i&gt;&lt;sup&gt;MUT&lt;/sup&gt; 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 &lt;i&gt;PTEN&lt;/i&gt;&lt;sup&gt;LOF&lt;/sup&gt;&lt;i&gt;/BRAF&lt;/i&gt;&lt;sup&gt;MUT&lt;/sup&gt; melanoma. Large-scale compound sensitivity profiling revealed that &lt;i&gt;PTEN&lt;/i&gt;&lt;sup&gt;LOF&lt;/sup&gt; 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 &lt;i&gt;PTEN&lt;/i&gt;&lt;sup&gt;LOF&lt;/sup&gt;&lt;i&gt;/BRAF&lt;/i&gt;&lt;sup&gt;MUT&lt;/sup&gt; 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 &lt;i&gt;PTEN&lt;/i&gt;&lt;sup&gt;LOF&lt;/sup&gt;&lt;i&gt;/BRAF&lt;/i&gt;&lt;sup&gt;MUT&lt;/sup&gt; melanoma patients to achieve maximal response. &lt;i&gt;Cancer Res; 76(2); 390–402. ©2015 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;