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. 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.

Automated summary

Uveal melanoma (UM) is a common eye cancer in adults, with up to 50% of patients developing metastases. A preclinical study showed that combining CDK4/6 inhibitor with cMET inhibitor could provide significant clinical benefit to patients with metastatic uveal melanoma by suppressing tumor growth.