title: Genotype-selective combination therapies for melanoma identified by high-throughput drug screening.
abstract: Resistance and partial responses to targeted monotherapy are major obstacles in cancer treatment. Systematic approaches to identify efficacious drug combinations for cancer are not well established, especially in the context of genotype. To address this, we have tested pairwise combinations of an array of small-molecule inhibitors on early-passage melanoma cultures using combinatorial drug screening. Results reveal several inhibitor combinations effective for melanomas with activating RAS or BRAF mutations, including mutant BRAF melanomas with intrinsic or acquired resistance to vemurafenib. Inhibition of both EGF receptor and AKT sensitized treatment-resistant BRAF mutant melanoma cultures to vemurafenib. Melanomas with RAS mutations were more resistant to combination therapies relative to BRAF mutants, but were sensitive to combinations of statins and cyclin-dependent kinase inhibitors in vitro and in vivo. These results show the use of combinatorial drug screening for discovering unique treatment regimens that overcome resistance phenotypes of mutant BRAF- and RAS-driven melanomas.
  
  
  CONCLUSIONS
  We have used drug combinatorial screening to identify effective combinations for mutant BRAF melanomas, including those resistant to vemurafenib, and mutant RAS melanomas that are resistant to many therapies. Mechanisms governing the interactions of the drug combinations are proposed, and in vivo xenografts show the enhanced benefit and tolerability of a mutant RAS -selective combination, which is currently lacking in the clinic.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Held
authors.forename: Casey G
authors.initials: CG
authors.lastname: Langdon
authors.forename: James T
authors.initials: JT
authors.lastname: Platt
authors.forename: Tisheeka
authors.initials: T
authors.lastname: Graham-Steed
authors.forename: Zongzhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Ashok
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Antonella
authors.initials: A
authors.lastname: Bacchiocchi
authors.forename: Andrew
authors.initials: A
authors.lastname: Koo
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Haskins
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Bosenberg
authors.forename: David F
authors.initials: DF
authors.lastname: Stern
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D011905:Genes, ras / Q000235:genetics; D057166:High-Throughput Screening Assays; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins