title: BRAF Inhibition Decreases Cellular Glucose Uptake in Melanoma in Association with Reduction in Cell Volume.
abstract: BRAF kinase inhibitors have dramatically affected treatment of BRAF(V600E) (/) (K)-driven metastatic melanoma. Early responses assessed using [(18)F]fluorodeoxyglucose uptake-positron emission tomography (FDG-PET) have shown dramatic reduction of radiotracer signal within 2 weeks of treatment. Despite high response rates, relapse occurs in nearly all cases, frequently at sites of treated metastatic disease. It remains unclear whether initial loss of (18)FDG uptake is due to tumor cell death or other reasons. Here, we provide evidence of melanoma cell volume reduction in a patient cohort treated with BRAF inhibitors. We present data demonstrating that BRAF inhibition reduces melanoma glucose uptake per cell, but that this change is no longer significant following normalization for cell volume changes. We also demonstrate that volume normalization greatly reduces differences in transmembrane glucose transport and hexokinase-mediated phosphorylation. Mechanistic studies suggest that this loss of cell volume is due in large part to decreases in new protein translation as a consequence of vemurafenib treatment. Ultimately, our findings suggest that cell volume regulation constitutes an important physiologic parameter that may significantly contribute to radiographic changes observed in clinic.
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut. nicholas.theodosakis@yale.edu.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Theodosakis
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Held
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Alexander
authors.initials: A
authors.lastname: Marzuka-Alcala
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Meeth
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Goran
authors.initials: G
authors.lastname: Micevic
authors.affiliation: Melanoma Institute of Australia, Sydney, New South Wales, Australia. Discipline of Pathology, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Melanoma Institute of Australia, Sydney, New South Wales, Australia. Discipline of Medicine, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: David F
authors.initials: DF
authors.lastname: Stern
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut. Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Bosenberg
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D048429:Cell Size; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism / Q000493:pharmacokinetics; D005947:Glucose / Q000378:metabolism* / Q000493:pharmacokinetics; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D013449:Sulfonamides; D019788:Fluorodeoxyglucose F18; D000077484:Vemurafenib; D006593:Hexokinase; D048493:Proto-Oncogene Proteins B-raf; D005947:Glucose