Selumetinib-based therapy in uveal melanoma patient-derived xenografts

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.

Preclinical evaluation of drug combinations identifies co-inhibition of Bcl-2/XL/W and MDM2 as a potential therapy in uveal melanoma

“…The main molecular features of these models are presented in the Supplementary Table S4. The experimental protocol of the in vivo study is detailed in the supplementary methods [10,30].…”

“…Previous studies have shown that UM cell lines and patient-derived xenografts (PDXs) are susceptible to inhibition of single pathways such as PKC or mitogenactivated protein kinase kinase (MEK) [8,10,11]. However, clinical trials relying on monotherapeutic strategies have not resulted in any significant benefit in terms of overall survival of UM patients [12e14].…”

Uveal melanoma: progress in molecular biology and therapeutics

“…An objective response rate (ORR) below −0.5 was achieved in all five models for both combination groups. 178 Recently, a review of 590 cases from six eligible clinical studies has shown that UM is poorly responsive to MEK inhibitors, including selumetinib [median PFS 16 weeks, median OS 11.8 months, 14% partial response (PR), 1-year OS rate 45% 176 ], trametinib (median PFS 1.8 months, ORR/PR/complete response 0% 179 ), and combined applications (selumetinib + dacarbazine: median PFS 2.8 months, 1-year OS rate 50%, ORR 3%; 180 trametinib + AKT inhibitor uprosertib: median PFS 15.7 weeks; 181 binimetinib + PKC inhibitor sotrastaurin: median PFS 3.1–4 weeks) [ClinicalTrials.gov identifier: NCT01801358]. 182 A recent three-arm randomized phase II study has demonstrated a statistically significant improvement in PFS for metastatic UM, from 3.4 months for selumetinib alone to 4.8 months for selumetinib in combination with paclitaxel (PT), without a significant increase in toxicity [ISRCTN 29621851].…”

PARP Inhibition Increases the Response to Chemotherapy in Uveal Melanoma

“…Various olaparib-based combinations with chemotherapies or targeted therapies were tested in 11 unique well-characterized UM PDXs (Table S2) that were already used for pharmacological assessments [11,12,25,26,27] and that well reproduce patients’ tumors [28,29].…”

“…Nevertheless, the MEK1/2 inhibitor selumetinib, in combination with dacarbazine, fails to improve progression-free survival of metastatic UM [10]. Various targeted therapies have therefore been tested in combination with selumetinib [11] or with the PKC (protein kinase C) inhibitor AEB071 [12] in UM preclinical models, and particularly in patient-derived xenografts (PDXs). On this basis, this last compound is currently being tested in a clinical trial, currently in combination with a MDM2 inhibitor (NCT02601378).…”