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.
Highlights
There is a wealth of genetic information characterizing uveal melanoma (UM) biology [1, 2]
A weak synergistic effect of the combination was observed in five of the six cell lines. This effect was observed at a concentration of 1.2 mM DTIC in MP38, MP41, and MP46 cells, and at 2.5 mM DTIC in MM28 and MP65 cells, for all concentrations of selumetinib tested
We used UM Patient Derived Xenograft (PDX) to evaluate the efficacy of the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib, alone or in combination with cytotoxic and targeted therapies
Summary
There is a wealth of genetic information characterizing uveal melanoma (UM) biology [1, 2]. GNAQ/11 mutations induce the constitutive activation of the PKC/MAPK pathways involved in oncogenesis [6,7,8]. Genotypedependent anti-tumor effects of MAPK pathway inhibition have been observed, acting at the level of the mitogenactivated protein kinase enzymes MEK1 and MEK2 in preclinical models [8, 9]. The first phase II clinical trial for selumetinib assessed the efficacy of this drug for uveal melanoma treatment through comparisons with temozolomide and dacarbazine [10]. The SUMIT phase III trial compared the efficacy of selumetinib with that of temozolomide or dacarbazine, with a view to improving clinical outcomes in patients [11]. The combinations tested did not improve PFS in patients with metastatic uveal melanoma. New therapeutic approaches are required, to achieve significant improvements in outcome in patients with metastatic UM
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