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

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.

• Authors: Kevin J Basile, Ethan V Abel, Neda Dadpey, Edward J Hartsough, Paolo Fortina, Andrew E Aplin
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 23 Pg. 7101-10 (Dec 01 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 24121492 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Indoles
• PLX 4720
• Sulfonamides
• enhanced green fluorescent protein
• Green Fluorescent Proteins
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Animals
• Drug Resistance, Neoplasm (genetics)
• Enzyme Activation (genetics)
• Female
• Genes, Reporter (physiology)
• Genetic Heterogeneity (drug effects)
• Green Fluorescent Proteins (genetics, metabolism)
• Humans
• Indoles (therapeutic use)
• MAP Kinase Signaling System (genetics)
• Mice
• Mice, Nude
• Mice, Transgenic
• Neoplasms (drug therapy, genetics, metabolism)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)
• Selection, Genetic (physiology)
• Sulfonamides (therapeutic use)
• Transfection
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays