Abstract
<div>Abstract<p><b>Purpose:</b> Vemurafenib, a selective inhibitor of <i>BRAF<sup>V600</sup></i>, has shown significant activity in <i>BRAF<sup>V600</sup></i> melanoma but not in less than 10% of metastatic <i>BRAF<sup>V600</sup></i> colorectal cancers (CRC), suggesting that studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAF<sup>mut</sup> CRC may provide combinatorial strategies.</p><p><b>Experimental Design:</b> We conducted comparative proteomic analysis of <i>BRAF<sup>V600E</sup></i> melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines and murine models.</p><p><b>Results:</b> Compared with melanoma, CRC lines show higher levels of PI3K/AKT pathway activation. CRC cell lines with mutations in <i>PTEN</i> or <i>PIK3CA</i> were less sensitive to growth inhibition by PLX4720 (<i>P</i> = 0.03), and knockdown of PTEN expression in sensitive CRC cells reduced growth inhibition by the drug. Combined treatment of PLX4720 with PI3K inhibitors caused synergistic growth inhibition in BRAF-mutant CRC cells with both primary and secondary resistance. In addition, methyltransferase inhibition was synergistic with PLX4720 and decreased AKT activation. <i>In vivo</i>, PLX4720 combined with either inhibitors of AKT or methyltransferase showed greater tumor growth inhibition than PLX4720 alone. Clones with acquired resistance to PLX4720 <i>in vitro</i> showed PI3K/AKT activation with EGF receptor (EGFR) or KRAS amplification.</p><p><b>Conclusions:</b> We show that activation of the PI3K/AKT pathway is a mechanism of both innate and acquired resistance to BRAF inhibitors in <i>BRAF<sup>V600E</sup></i> CRC and suggest combinatorial approaches to improve outcomes in this poor prognosis subset of patients. <i>Clin Cancer Res; 19(3); 657–67. ©2012 AACR</i>.</p></div>
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
