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

Authors

Masahiro Ohara, Department of Medical Oncology, Thomas Jefferson University, 1015 Walnut Street, Suite 1024, Philadelphia, PA 19107, United States; Department of Breast Surgery, Hiroshima General Hospital, 1‐3‐3 Jigozen, Hiroshima, Hatsukaichi, 738‐8503, JapanFollow
Kengo Saito, Department of Medical Oncology, Thomas Jefferson University, 1015 Walnut Street, Suite 1024, Philadelphia, PA 19107, United States; Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1‐8‐1 Inohana, Chuou‐ku, Chiba, 260‐8670, Japan
Ken Kageyama, Department of Medical Oncology, Thomas Jefferson University, 1015 Walnut Street, Suite 1024, Philadelphia, PA 19107, United States; Department of Radiology, Osaka City University, 1‐4‐3 Asahimachi, Abeno‐ku, Osaka, 545‐8585, JapanFollow
Mizue Terai, Department of Medical Oncology, Thomas Jefferson University, 1015 Walnut Street, Suite 1024, Philadelphia, PA 19107, United StatesFollow
Hanyin Cheng, Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United States; Hematologics Inc., 3161 Elliott Ave., Suite 200, Seattle, WA 98121, United StatesFollow
A E Aplin, Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, United StatesFollow
Takami Sato, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PAFollow

Document Type

Article

Publication Date

3-4-2021

Comments

This article has been peer reviewed. It was published in: Cancers.

The published version is available at DOI: 10.3390/cancers13051104

Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

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.

Recommended Citation

Ohara, Masahiro; Saito, Kengo; Kageyama, Ken; Terai, Mizue; Cheng, Hanyin; Aplin, A E; and Sato, Takami, "Dual Targeting of CDK4/6 and cMET in Metastatic Uveal Melanoma." (2021). Department of Medical Oncology Faculty Papers. Paper 137.
https://jdc.jefferson.edu/medoncfp/137

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

33806615