Description:
<jats:title>Abstract</jats:title>
<jats:p>Uveal melanoma is one of most common intraocular malignancies of the adult eye. GNAQ/ GNA11 genetic alterations are present in 85% of diagnosed cases resulting in activation of MAPK pathway. Recently, MEK inhibitors, such as selumetinib have been used to treat GNAQ/GNA11-mutant uveal melanoma patients. However, selumetinib has shown modest effect compared to chemotherapy. As ERK is the primary downstream effector of the MAPK pathway, it is hypothesized that ERK inhibitors have the potential to improve clinical activity in these patient populations. We examined the effects of a selective and potent ERK inhibitor (Compound A), on several uveal melanoma cell lines including 4 GNAQ cell lines (92.1, Mel202, Omm1.3, MP46), 2 GNA11 cell lines (MP41, Omm1), 2 BRAF cell lines (OCM1A, OCM1) and a Wild Type (Mel290) cell line. The uveal melanoma cell lines were sensitive to ERK inhibition by Compound A, with IC50s concentrations determined to be between 50 to 250 nM. Compound A was more effective at inhibiting growth than the MEK inhibitor selumetinib at nanomolar concentrations. Compound A at 250 nM inhibited pERK1/2 within at least 2 hours of drug exposure. By 24 hours inhibition of pRB and suppression of cyclin D1 was detected in all the cell lines tested except the Wild type cell line Mel290. Cell cycle analysis of Compound A dosed at 250 nM for 24 hours showed significant G1 arrest (85-90% G1). These in vitro results support further evaluation of ERK inhibition in the treatment of uveal melanoma.</jats:p>
<jats:p>Citation Format: Elgilda Musi, Grazia Ambrosini, Joanne Munck, Gary K. Schwartz. A novel ERK inhibitor in the treatment of uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5784.</jats:p>