Cancer Cell, 01/2015, Vol.27(1), pp.85-96
To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ccell.2014.11.006 Byline: Maria Romina Girotti, Filipa Lopes, Natasha Preece, Dan Niculescu-Duvaz, Alfonso Zambon, Lawrence Davies, Steven Whittaker, Grazia Saturno, Amaya Viros, Malin Pedersen, Bart M.J.M. Suijkerbuijk, Delphine Menard, Robert McLeary, Louise Johnson, Laura Fish, Sarah Ejiama, Berta Sanchez-Laorden, Juliane Hohloch, Neil Carragher, Kenneth Macleod, Garry Ashton, Anna A. Marusiak, Alberto Fusi, John Brognard, Margaret Frame, Paul Lorigan, Richard Marais, Caroline Springer 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. Author Affiliation: (1) Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK (2) Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK (3) Targeted Therapy Team, The Institute of Cancer Research, London SW3 6JB, UK (4) Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK (5) Histology Unit, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK (6) Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK (7) University of Manchester, Christie NHS Foundation Trust, Manchester M20 4BX, UK Article History: Received 17 May 2014; Revised 11 August 2014; Accepted 7 November 2014 Article Note: (footnote) This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
Drug Resistance – Drug Therapy ; Melanoma – Drug Therapy;