title: Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy.
abstract: Once melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant melanoma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could improve current approaches of targeted melanoma therapy.
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Smith
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Holly
authors.initials: H
authors.lastname: Brunton
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Rowling
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ferguson
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Imanol
authors.initials: I
authors.lastname: Arozarena
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Miskolczi
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Lee
authors.affiliation: Molecular Oncology Group, CRUK Manchester Institute for Cancer Research, Manchester Cancer Research Centre, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Girotti
authors.affiliation: Molecular Oncology Group, CRUK Manchester Institute for Cancer Research, Manchester Cancer Research Centre, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.affiliation: Department of Dermatology, UniversitätsSpital Zürich, University of Zürich, Gloriastrasse 31, 8091 Zurich, Switzerland.
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Levesque
authors.affiliation: Department of Dermatology, UniversitätsSpital Zürich, University of Zürich, Gloriastrasse 31, 8091 Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114-2696, USA.
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114-2696, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Divison of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX 77030, USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: Divison of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX 77030, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Manchester Cancer Research Centre, Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK. Electronic address: claudia.wellbrock@manchester.ac.uk.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wellbrock
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004361:Drug Tolerance / Q000235:genetics*; D020558:GTP Phosphohydrolases / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000187:drug effects* / Q000235:genetics*; D019888:Nelfinavir / Q000494:pharmacology; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D017320:HIV Protease Inhibitors; D008565:Membrane Proteins; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D019888:Nelfinavir