Abstract 911: Vemurafenib FDG-PET preclinical imaging outcomes across BRAF V600E mutant and resistant tumors

Abstract

Abstract The BRAF inhibitor vemurafenib (marketed as zelboraf) has recently been FDA approved for the treatment of metastatic melanoma in patients harboring BRAF V600 mutations. PET imaging will be essential for guiding therapy in terms of gauging initial drug response, monitoring for disease relapse, and evaluating combination treatments in clinical trials. Herein, we assess 18F-FDG uptake across V600E mutant and vemurafenib resistant cells. We find that vemurafenib is equally effective at reducing FDG uptake in cell lines harboring either heterozygous or homozygous V600E BRAF but is ineffective in cells with acquired resistance or BRAF WT cells. Combination treatment with MEK inhibitor GDC-0973 results in a highly significant enhancement of efficacy across all twenty lines tested. We show that FDG uptake is driven by Glut-1, and that the membrane localization of the transporter paralleled with drug efficacy. Interestingly, we find that vemurafenib induced increased FDG uptake in cells harboring RAS mutations, as well as in tumors that have acquired vemurafenib drug resistance. Hexokinase II, CRAF, KSR and p-MEK protein levels in sensitive and drug resistant tumors were all associated with decreased measurements of FDG uptake in vivo. Overall, we have demonstrated that FDG PET imaging should be effective at monitoring the efficacy of vemurafenib in V600E melanoma mutants and that any detected increases in tumor uptake will likely be an indication of drug resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 911. doi:1538-7445.AM2012-911