title: Dependence On Glycolysis Sensitizes BRAF-mutated Melanomas For Increased Response To Targeted BRAF Inhibition.
abstract: Dysregulated metabolism can broadly affect therapy resistance by influencing compensatory signaling and expanding proliferation. Given many BRAF-mutated melanoma patients experience disease progression with targeted BRAF inhibitors, we hypothesized therapeutic response is related to tumor metabolic phenotype, and that altering tumor metabolism could change therapeutic outcome. We demonstrated the proliferative kinetics of BRAF-mutated melanoma cells treated with the BRAF inhibitor PLX4720 fall along a spectrum of sensitivity, providing a model system to study the interplay of metabolism and drug sensitivity. We discovered an inverse relationship between glucose availability and sensitivity to BRAF inhibition through characterization of metabolic phenotypes using nearly a dozen metabolic parameters in Principle Component Analysis. Subsequently, we generated rho0 variants that lacked functional mitochondrial respiration and increased glycolytic metabolism. The rho0 cell lines exhibited increased sensitivity to PLX4720 compared to the respiration-competent parental lines. Finally, we utilized the FDA-approved antiretroviral drug zalcitabine to suppress mitochondrial respiration and to force glycolysis in our cell line panel, resulting in increased PLX4720 sensitivity via shifts in EC50 and Hill slope metrics. Our data suggest that forcing tumor glycolysis in melanoma using zalcitabine or other similar approaches may be an adjunct to increase the efficacy of targeted BRAF therapy.
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.|Center for Cancer Systems Biology at Vanderbilt, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.
authors.forename: Keisha N
authors.initials: KN
authors.lastname: Hardeman
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.|Center for Cancer Systems Biology at Vanderbilt, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.
authors.forename: Chengwei
authors.initials: C
authors.lastname: Peng
authors.affiliation: Center for Cancer Systems Biology at Vanderbilt, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.|Chemical and Physical Biology Graduate Program, Vanderbilt University, Nashville, TN, 37232, USA.
authors.forename: Bishal B
authors.initials: BB
authors.lastname: Paudel
authors.affiliation: Center for Cancer Systems Biology at Vanderbilt, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Meyer
authors.affiliation: Departments of Medicine &Pharmacology, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, 21st Avenue South, Nashville, TN 37232, USA.
authors.forename: Thong
authors.initials: T
authors.lastname: Luong
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.|Center for Cancer Systems Biology at Vanderbilt, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Tyson
authors.affiliation: Departments of Chemical Biomolecular Engineering, and Molecular Physiology &Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Jamey D
authors.initials: JD
authors.lastname: Young
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.|Center for Cancer Systems Biology at Vanderbilt, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.
authors.forename: Vito
authors.initials: V
authors.lastname: Quaranta
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA.|Departments of Medicine &Pharmacology, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, 21st Avenue South, Nashville, TN 37232, USA.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Fessel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009154:Mutation; D009857:Oncogenes; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D048493:Proto-Oncogene Proteins B-raf; D005947:Glucose