title: B-Raf inhibitor vemurafenib in combination with temozolomide and fotemustine in the killing response of malignant melanoma cells.
abstract: In the treatment of metastatic melanoma, a highly therapy-refractory cancer, alkylating agents are used and, for the subgroup of BRAFV600E cancers, the B-Raf inhibitor vemurafenib. Although vemurafenib is initially beneficial, development of drug resistance occurs leading to tumor relapse, which necessitates the requirement for combined or sequential therapy with other drugs, including genotoxic alkylating agents. This leads to the question whether vemurafenib and alkylating agents act synergistically and whether chronic vemurafenib treatment alters the melanoma cell response to alkylating agents. Here we show that a) BRAFV600E melanoma cells are killed by vemurafenib, driving apoptosis, b) BRAFV600E melanoma cells are neither more resistant nor sensitive to temozolomide/fotemustine than non-mutant cells, c) combined treatment with vemurafenib plus temozolomide or fotemustine has an additive effect on cell kill, d) acquired vemurafenib resistance of BRAFV600E melanoma cells does not affect MGMT, MSH2, MSH6, PMS2 and MLH1, nor does it affect the resistance to temozolomide and fotemustine, e) metastatic melanoma biopsies obtained from patients prior to and after vemurafenib treatment did not show a change in the MGMT promoter methylation status and MGMT expression level. The data suggest that consecutive treatment with vemurafenib and alkylating drugs is a reasonable strategy for metastatic melanoma treatment.
authors.affiliation: Institute of Toxicology, Medical University Center, Mainz, Germany.
authors.forename: Wynand P
authors.initials: WP
authors.lastname: Roos
authors.affiliation: Institute of Toxicology, Medical University Center, Mainz, Germany.
authors.forename: Steve
authors.initials: S
authors.lastname: Quiros
authors.affiliation: Institute of Toxicology, Medical University Center, Mainz, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Krumm
authors.affiliation: Institute of Toxicology, Medical University Center, Mainz, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Merz
authors.affiliation: Institute of Toxicology, Medical University Center, Mainz, Germany.
authors.forename: Olivier Jérôme
authors.initials: OJ
authors.lastname: Switzeny
authors.affiliation: Institute of Toxicology, Medical University Center, Mainz, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Christmann
authors.affiliation: Department of Dermatology, Medical University Center, Mainz, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Loquai
authors.affiliation: Institute of Toxicology, Medical University Center, Mainz, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009607:Nitrosourea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D000077204:Temozolomide; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D013449:Sulfonamides; D000077484:Vemurafenib; D003606:Dacarbazine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C054368:fotemustine; D000077204:Temozolomide