Abstract 2301: Dual targeting of CDK4/6 and MET in metastatic uveal melanoma

Abstract

Abstract Uveal melanoma (UM) is the most common cancer of the eye in adults. Up to 50% of UM patients subsequently develop metastases, especially in the liver, for which no effective treatment has been identified. It has been reported that the retinoblastoma (RB) pathway is deregulated in more than 90% of UM despite the rarity of mutations in the RB1 gene itself. Cyclin D1 over-expression and inactivation of p16INK4a in UM are frequently present and make the RB protein constitutively hyperphosphorylated and functionally inactivated; therefore, CDK4/6 inhibition (CDK4/6i) is a rational strategy for treatment of UM. In this report, we investigated the antiproliferative activity of a selective CDK4/6 inhibitor on metastatic UM. A CDK4/6 inhibitor induced G0-G1 arrest in all three metastatic UM cell lines and suppressed their growth in in vitro and in vivo experiments. Interestingly, hepatocyte growth factor (HGF) decreased the effect of CDK4/6 inhibitor on metastatic UM cell lines and protected the metastatic UM cells from CDK4/6 inhibitor-induced cellular senescence. When CDK4/6i was combined with MET inhibitor, enhanced growth suppression was observed in metastatic UM tumors grown in human-HGF knock-in xenograft mouse models. HGF is enriched in the liver and the majority of liver metastases from UM express activated forms of MET; therefore, signaling through MET could contribute to the resistance mechanisms against CDK4/6i, especially in UM patients with hepatic metastasis. Together, these results provide a rationale for the use of MET inhibitor in combination with a CDK4/6 inhibitor for the treatment of metastatic UM. Citation Format: Masahiro Ohara, Kengo Saito, Ken Kageyama, Mizue Terai, Hanyin Cheng, Andrew E. Aplin, Takami Sato. Dual targeting of CDK4/6 and MET in metastatic 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 2301.