Selumetinib-based therapy in uveal melanoma patient-derived xenografts

// Didier Decaudin 1, 2 , Rania El Botty 1 , Béré Diallo 1 , Gerald Massonnet 1 , Justine Fleury 1 , Adnan Naguez 1 , Chloé Raymondie 1 , Emma Davies 3 , Aaron Smith 3 , Joanne Wilson 3 , Colin Howes 3 , Paul D. Smith 3 , Nathalie Cassoux 4 , Sophie Piperno-Neumann 2 , Sergio Roman-Roman 5 and Fariba Némati 1 1 Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University Paris, Paris, France 2 Department of Medical Oncology, Institut Curie, Paris, France 3 IMED Oncology, AstraZeneca, Cambridge, UK 4 Department of Oncological Ophthalmology, Institut Curie, Paris, France 5 Department of Translational Research, Institut Curie, PSL University Paris, Paris, France Correspondence to: Fariba Némati, email: fariba.nemati@curie.fr Keywords: uveal melanoma; patient-derived xenografts; selumetinib; targeted therapies; pharmacodynamics Received: September 19, 2017 Accepted: February 26, 2018 Published: April 24, 2018 ABSTRACT The prognosis of metastatic uveal melanoma (UM) is among the worst of all human cancers. The identification of near-ubiquitous GNAQ/GNA11 mutations and the activation of MAPK signaling in UM have raised hopes of more effective, targeted therapies, based on MEK inhibition, for example. We evaluated the potential of drug combinations to increase the efficacy of the MEK inhibitor selumetinib (AZD6244, ARRY-142886), in UM cell lines and Patient-Derived Xenografts. We first evaluated the combination of selumetinib and DTIC. We found that DTIC did not improve the in vitro or in vivo antitumor efficacy of selumetinib, consistent with the outcome of the SUMIT clinical trial assessing the efficacy of this combination in UM. We then tested additional selumetinib combinations with the chemotherapy agent docetaxel, the ERK inhibitor AZ6197, and the mTORC1/2 inhibitor, vistusertib (AZD2014). Combinations of selumetinib with ERK and mTORC1/2 inhibitors appeared to be the most effective in UM PDX models.