Dual Targeting of CDK4/6 and cMET in Metastatic Uveal Melanoma
Department of Medical Oncology, Thomas Jefferson University, 1015 Walnut Street, Suite 1024, Philadelphia, PA 19107, USA
Department of Breast Surgery, Hiroshima General Hospital, 1-3-3 Jigozen, Hatsukaichi, Hiroshima 738-8503, Japan
Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan
Department of Radiology, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
Hematologics Inc., 3161 Elliott Ave., Suite 200, Seattle, WA 98121, USA
Author to whom correspondence should be addressed.
Academic Editor: Ellen Kapiteijn
Received: 25 January 2021
Revised: 25 February 2021
Accepted: 27 February 2021
Published: 4 March 2021
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.