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

Abstract

Introduction: Uveal melanoma (UM) is a rare and malignant intraocular tumour with a dismal prognosis. Despite a good control of the primary tumour by radiation or surgery, up to 50% of patients subsequently develop metastasis for which no efficient treatment is yet available. Methodology: To identify therapeutic opportunities, we performed an in vitro screen of 30 combinations of different inhibitors of pathways that are dysregulated in UM. Effects of drug combinations on viability, cell cycle and apoptosis were assessed in eight UM cell lines. The best synergistic combinations were further evaluated in six UM patient-derived xenografts (PDXs). Results: We demonstrated that the Bcl-2/X L /W inhibitor (ABT263) sensitised the UM cell lines to other inhibitors, mainly to mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase (MEK) and murine double minute 2 (MDM2) inhibitors. mTOR (RAD001) and MEK1/2 (trametinib) inhibitors were efficient as single agents, but their combinations with ABT263 displayed no synergism in UM PDXs. In contrast, the combination of

Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

“…However, no particular correlation with histomorphological or genetic features of the tumours nor with clinical outcome have been reported. Although not previously investigated in such a large patient mUM cohort until the current study, BCL2 has been the subject of studies to improve the cytotoxic effect of different chemotherapeutics against UM cells in preclinical settings [ 103 , 104 , 105 , 106 ]. Indeed, Decaudin et al performed a comprehensive preclinical screening of a panel of 5 different BCL2 protein family inhibitors and assessed their synergy with PI3K/AKT/mTOR, p53, and MAPK/ERK inhibitors against both primary and metastatic UM cell lines.…”

“…Several combinations showed a synergetic effect, and the most promising combinations were further assessed in patient-derived xenograft (PDX) models. The BCL-2/XL/W inhibitor (ABT263) combined with MDM2 inhibitor (HDM201) showed a trend for a synergistic effect in the PDX models [ 106 ]. However, further studies employing BCL-2 in the context of mUM are required considering data that suggest high galectin-3 expression, as seen in mUM, may mediate resistance to BCL-2 targeted therapies [ 107 ].…”

Patient-derived zebrafish xenograft models reveal ferroptosis as a fatal and druggable weakness in metastatic uveal melanoma

“…These therapeutics or combinatorial therapies were originally selected through a combination of genomic analysis, in vitro pre-screening and an efficacy study in a murine subcutaneous UM PDX model, derived from the same metastatic UM patient (Xmm66 tissue) 23 . We used spXmm66-derived cells engrafted in zebrafish and tested three combinatorial sets of small molecule inhibitors, previously published, as a means of chemical validation of the zf-PDX model 25,38,39 . The spXmm66 engrafted zebrafish were exposed to: mTORC1 inhibitor-everolimus (RAD001) together with PKC inhibitor-sotrastaurin (AEB071), BCL-2/BCL-xl inhibitor-navitoclax (ABT263) combined with RAD001 and HDAC inhibitor-quisinostat, and with CDK inhibitorflavopiridol (Figure 4).…”

“…Paradoxically, in contrast to the lethal nature of metastatic UM, no reproducible metastatic xenograft models have been established that are suitable for drug screening. Recently generated, patient-derived murine xenograft (PDX) models have been used to screen new drug combinations [23][24][25] ; however, the PDXs are commonly grown subcutaneously and do not resemble dissemination of metastatic disease.…”

Hindsight: Review of Preclinical Disease Models for the Development of New Treatments for Uveal Melanoma

“…Despite a small number of experiments showing anti-tumour activity and reduction in tumour volume, selumetinib monotherapy, or in combination with dacarbazine (DTIC) or AKT inhibitor, did not cause a significant objective response (OR) in the chosen experimental models 90 , 91 . The MEK 1/2 inhibitor trametinib alone did not induce anti-proliferative effects in UM cell lines 92 , in vitro studies in combination with ABT263 were synergistic, however this combination did not show anti-tumoral effects in PDX in vivo models 93 . Furthermore, phase II clinical trials of trametinib in combination with AKT inhibitor GSK2141795 did not improve PFS in advanced UM 94 .…”