Pan-RAF inhibitor active in melanomas that are resistant to BRAF or BRAF /MEK inhibitor combinations.


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Maria Romina Girotti1, Filipa Lopes2, Natasha Preece2, Dan Niculescu-Duvaz2, Alfonso Zambon2, Lawrence Davies2, Steven Whittaker2, Grazia Saturno1, Amaya Viros1, Malin Pedersen4, McLeary Robert2, Johnson Louise2, Fish Laura2, Ejiama Sarah1, Marusiak Anna A3, Fusi Alberto5, John Brognard3, Paul Lorigan5, Caroline Springer2, Richard Marais1
1Molecular Oncology Group - Cancer Research UK Manchester Institute, Manchester, UK,2Gene and Oncogene Targeting Team - The Institute of Cancer Research, London, UK,3Signal Transduction Team - Cancer Research UK Manchester Institute, Manchester, UK,4Targeted Therapy Team - The Institute of Cancer Research, London, UK,5University of Manchester - Christie NHS Foundation Trust, Manchester, UK

Abstract

Background

The protein kinase BRAF is mutated  ~40% of human melanomas.  BRAF is a component of the RAS/RAF/MEK/ERK pathway and BRAF or MEK inhibitors increase progression-free and  overall  survival  in  melanoma  patients  with  BRAF mutations.  However, most patients relapse with acquired resistance and ~20% of patients present intrinsic resistance and do not respond to these drugs.