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Clin Cancer Res. 2017 Jun 15;23(12):3181-3190. doi: 10.1158/1078-0432.CCR-17-0201. Epub 2017 Feb 23.

Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho.

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The Wistar Institute, Philadelphia, Pennsylvania.
University of the Sciences, Philadelphia, Pennsylvania.
University of Zurich, Zurich, Switzerland.
Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania.
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Department of Dermatology, University Hospital, West German Cancer Center, University Duesburg-Essen, Essen, Germany.
The Wistar Institute, Philadelphia, Pennsylvania.


Purpose: Aging is a poor prognostic factor for melanoma. We have shown that melanoma cells in an aged microenvironment are more resistant to targeted therapy than identical cells in a young microenvironment. This is dependent on age-related secreted factors. Klotho is an age-related protein whose serum levels decrease dramatically by age 40. Most studies on klotho in cancer have focused on the expression of klotho in the tumor cell. We have shown that exogenous klotho inhibits internalization and signaling of Wnt5A, which drives melanoma metastasis and resistance to targeted therapy. We investigate here whether increasing klotho in the aged microenvironment could be an effective strategy for the treatment of melanoma.Experimental Design: PPARγ increases klotho levels and is increased by glitazones. Using rosiglitazone, we queried the effects of rosiglitazone on Klotho/Wnt5A cross-talk, in vitro and in vivo, and the implications of that for targeted therapy in young versus aged animals.Results: We show that rosiglitazone increases klotho and decreases Wnt5A in tumor cells, reducing the burden of both BRAF inhibitor-sensitive and BRAF inhibitor-resistant tumors in aged, but not young mice. However, when used in combination with PLX4720, tumor burden was reduced in both young and aged mice, even in resistant tumors.Conclusions: Using glitazones as adjuvant therapy for melanoma may provide a new treatment strategy for older melanoma patients who have developed resistance to vemurafenib. As klotho has been shown to play a role in other cancers too, our results may have wide relevance for multiple tumor types. Clin Cancer Res; 23(12); 3181-90. ©2017 AACR.

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