title: Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma.
abstract: BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
authors.forename: Maria Romina
authors.initials: MR
authors.lastname: Girotti
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Filipa
authors.initials: F
authors.lastname: Lopes
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Natasha
authors.initials: N
authors.lastname: Preece
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Dan
authors.initials: D
authors.lastname: Niculescu-Duvaz
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Zambon
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Davies
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Whittaker
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
authors.forename: Grazia
authors.initials: G
authors.lastname: Saturno
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
authors.forename: Amaya
authors.initials: A
authors.lastname: Viros
authors.affiliation: Targeted Therapy Team, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Malin
authors.initials: M
authors.lastname: Pedersen
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Bart M J M
authors.initials: BM
authors.lastname: Suijkerbuijk
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Delphine
authors.initials: D
authors.lastname: Menard
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: McLeary
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Johnson
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Fish
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ejiama
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
authors.forename: Berta
authors.initials: B
authors.lastname: Sanchez-Laorden
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
authors.forename: Juliane
authors.initials: J
authors.lastname: Hohloch
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Carragher
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Macleod
authors.affiliation: Histology Unit, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
authors.forename: Garry
authors.initials: G
authors.lastname: Ashton
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Marusiak
authors.affiliation: University of Manchester, Christie NHS Foundation Trust, Manchester M20 4BX, UK.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fusi
authors.affiliation: Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
authors.forename: John
authors.initials: J
authors.lastname: Brognard
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Frame
authors.affiliation: University of Manchester, Christie NHS Foundation Trust, Manchester M20 4BX, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Lorigan
authors.affiliation: Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK. Electronic address: richard.marais@cruk.manchester.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK. Electronic address: caroline.springer@icr.ac.uk.
authors.forename: Caroline
authors.initials: C
authors.lastname: Springer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008546:Melanoma, Experimental; D051379:Mice; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: C000595971:1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-(methylthio)-4-(3-oxo-3,4-dihydropyrido(2,3-b)pyrazin-8-yloxy)phenyl)urea; C000595970:1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(3-oxo-3,4-dihydropyrido(3,2-b)pyrazin-8-yloxy)phenyl)urea; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D019061:src-Family Kinases; D048493:Proto-Oncogene Proteins B-raf