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Cancer Res. 2013 Dec 1;73(23):7101-10. doi: 10.1158/0008-5472.CAN-13-1628. Epub 2013 Oct 11.

In vivo MAPK reporting reveals the heterogeneity in tumoral selection of resistance to RAF inhibitors.

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1
Authors' Affiliations: Departments of Cancer Biology, Medical Oncology, and Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.

Abstract

Activation of the ERK1/2 mitogen-activated protein kinases (MAPK) confers resistance to the RAF inhibitors vemurafenib and dabrafenib in mutant BRAF-driven melanomas. Methods to understand how resistance develops are important to optimize the clinical use of RAF inhibitors in patients. Here, we report the development of a novel ERK1/2 reporter system that provides a noninvasive, quantitative, and temporal analysis of RAF inhibitor efficacy in vivo. Use of this system revealed heterogeneity in the level of ERK1/2 reactivation associated with acquired resistance to RAF inhibition. We identified several distinct novel and known molecular changes in resistant tumors emerging from treatment-naïve cell populations including BRAF V600E variants and HRAS mutation, both of which were required and sufficient for ERK1/2 reactivation and drug resistance. Our work offers an advance in understanding RAF inhibitor resistance and the heterogeneity in resistance mechanisms, which emerge from a malignant cell population.

PMID:
24121492
PMCID:
PMC3851924
DOI:
10.1158/0008-5472.CAN-13-1628
[Indexed for MEDLINE]
Free PMC Article
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