title: Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho.
abstract: 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 vitroandin 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.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Reeti
authors.initials: R
authors.lastname: Behera
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.|University of the Sciences, Philadelphia, Pennsylvania.
authors.forename: Amanpreet
authors.initials: A
authors.lastname: Kaur
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Marie R
authors.initials: MR
authors.lastname: Webster
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Suyeon
authors.initials: S
authors.lastname: Kim
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.|University of the Sciences, Philadelphia, Pennsylvania.
authors.forename: Abibatou
authors.initials: A
authors.lastname: Ndoye
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Curtis H
authors.initials: CH
authors.lastname: Kugel
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.|University of the Sciences, Philadelphia, Pennsylvania.
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Alicea
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Joshua
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Kanad
authors.initials: K
authors.lastname: Ghosh
authors.affiliation: University of Zurich, Zurich, Switzerland.
authors.forename: Phil
authors.initials: P
authors.lastname: Cheng
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Sofia
authors.initials: S
authors.lastname: Lisanti
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Katie
authors.initials: K
authors.lastname: Marchbank
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Dang
authors.affiliation: University of Zurich, Zurich, Switzerland.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Levesque
authors.affiliation: University of Zurich, Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Aplin
authors.affiliation: Department of Dermatology, University Hospital, West German Cancer Center, University Duesburg-Essen, Essen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Roesch
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Caino
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania. aweeraratna@wistar.org.
authors.forename: Ashani T
authors.initials: AT
authors.lastname: Weeraratna
mesh_terms: D000328:Adult; D000367:Age Factors; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D000090265:Klotho Proteins; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D000077154:Rosiglitazone; D013449:Sulfonamides / Q000008:administration & dosage; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000009:adverse effects; D059016:Tumor Microenvironment / Q000187:drug effects; D000071818:Wnt-5a Protein / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; C528407:PLX 4720; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D045162:Thiazolidinediones; C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; D000077154:Rosiglitazone; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D005966:Glucuronidase; D000090265:Klotho Proteins