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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
Cancers 2021, 13(5), 1104;
Received: 25 January 2021 / Revised: 25 February 2021 / Accepted: 27 February 2021 / Published: 4 March 2021
(This article belongs to the Special Issue Metastatic Uveal Melanoma)
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. View Full-Text
Keywords: CDK4/6 inhibitor; cMET inhibitor; metastatic uveal melanoma; combination therapy; HGF CDK4/6 inhibitor; cMET inhibitor; metastatic uveal melanoma; combination therapy; HGF
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MDPI and ACS Style

Ohara, M.; Saito, K.; Kageyama, K.; Terai, M.; Cheng, H.; Aplin, A.E.; Sato, T. Dual Targeting of CDK4/6 and cMET in Metastatic Uveal Melanoma. Cancers 2021, 13, 1104.

AMA Style

Ohara M, Saito K, Kageyama K, Terai M, Cheng H, Aplin AE, Sato T. Dual Targeting of CDK4/6 and cMET in Metastatic Uveal Melanoma. Cancers. 2021; 13(5):1104.

Chicago/Turabian Style

Ohara, Masahiro, Kengo Saito, Ken Kageyama, Mizue Terai, Hanyin Cheng, Andrew E. Aplin, and Takami Sato. 2021. "Dual Targeting of CDK4/6 and cMET in Metastatic Uveal Melanoma" Cancers 13, no. 5: 1104.

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