Dual Targeting of CDK4/6 and cMET in Metastatic Uveal Melanoma

SIMPLE SUMMARY: Up to 50% of uveal melanoma patients subsequently develop metastases, for which no effective treatment has been identified. In this study, 87.5% of uveal melanoma patients’ samples were positive for phosphorylated retinoblastoma (RB), and ex vivo incubation of patients’ biopsy specimens with CDK4/6 inhibitor decreased the phosphorylation of RB. Hepatocyte growth factor (HGF), which is rich in the liver microenvironment, diminished the efficacy of CDK4/6 inhibitor. In human HGF knock-in NOD.Cg-Prkdc scid Il2rg tm1Wjl/SzJ mice, combination of CDK4/6 inhibitor and cMET inhibitor showed significant growth suppression in implanted metastatic uveal melanoma cells, compared to CDK4/6 inhibitor alone. Taken together, our preclinical study indicated that combining CDK4/6 inhibitor and cMET inhibitor would provide significant clinical benefit to patients with metastatic uveal melanoma. 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. 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. 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 suppressed UM cell lines growth in in vitro and in vivo experiments. Hepatocyte growth factor (HGF) decreased the effect of CDK4/6 inhibitor on metastatic UM cell lines. When CDK4/6i was combined with cMET 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 cMET; therefore, signaling through cMET 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 cMET inhibitor in combination with a CDK4/6 inhibitor for the treatment of metastatic UM.