title: 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.affiliation: Authors' Affiliations: Departments of Cancer Biology, Medical Oncology, and Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Basile
authors.forename: Ethan V
authors.initials: EV
authors.lastname: Abel
authors.forename: Neda
authors.initials: N
authors.lastname: Dadpey
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hartsough
authors.forename: Paolo
authors.initials: P
authors.lastname: Fortina
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Aplin
mesh_terms: D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D017930:Genes, Reporter / Q000502:physiology; D018740:Genetic Heterogeneity / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D012641:Selection, Genetic / Q000502:physiology; D013449:Sulfonamides / Q000627:therapeutic use*; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; C528407:PLX 4720; D013449:Sulfonamides; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf