Selumetinib-based therapy in uveal melanoma patient-derived xenografts
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Didier Decaudin1,2, Rania El Botty1, Béré Diallo1, Gerald Massonnet1, Justine Fleury1, Adnan Naguez1, Chloé Raymondie1, Emma Davies3, Aaron Smith3, Joanne Wilson3, Colin Howes3, Paul D. Smith3, Nathalie Cassoux4, Sophie Piperno-Neumann2, Sergio Roman-Roman5 and Fariba Némati1
1Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University Paris, Paris, France
2Department of Medical Oncology, Institut Curie, Paris, France
3IMED Oncology, AstraZeneca, Cambridge, UK
4Department of Oncological Ophthalmology, Institut Curie, Paris, France
5Department of Translational Research, Institut Curie, PSL University Paris, Paris, France
Fariba Némati, email: [email protected]
Keywords: uveal melanoma; patient-derived xenografts; selumetinib; targeted therapies; pharmacodynamics
Received: September 19, 2017 Accepted: February 26, 2018 Published: April 24, 2018
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.
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