Selumetinib-based therapy in uveal melanoma patient-derived xenografts

Oncotarget
Didier DecaudinFariba Némati

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.

References

Dec 17, 2008·Nature·Catherine D Van RaamsdonkBoris C Bastian
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Jan 25, 2012·Pigment Cell & Melanoma Research·J William Harbour
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Citations

May 31, 2019·Cancers·Leanne de KoningFariba Némati
Jun 21, 2019·Cancers·Michela CroceRosaria Gangemi
Sep 17, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Amanda TruongMartin McMahon
May 26, 2020·Seminars in Cancer Biology·Prisca BustamanteJulia V Burnier
Nov 6, 2020·Therapeutic Advances in Medical Oncology·Yongyun LiXianqun Fan

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Methods Mentioned

BETA
GTPases
xenografts
xenograft
electrophoresis

Software Mentioned

Multi Gauge

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