Rosiglitazone and Trametinib Exhibit Potent Anti-Tumor Activity in a Mouse Model of Muscle Invasive Bladder Cancer

Authors

Sakina A Plumber
Tiffany Tate
Hikmat Al-Ahmadie
Xiao Chen
Woonyoung Choi
Merve Basar
Chao Lu
Aaron Viny
Ekatherina Batourina
Jiaqi Li
Kristjan Gretarsson
Besmira Alija
Andrei Molotkov
Gregory Wiessner
Byron Hing Lung Lee
James McKiernan
David J McConkey
Colin Dinney
Bogdan Czerniak
Cathy Lee Mendelsohn

Publication Date

8-2-2024

Journal

Nature Communications

Abstract

Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.

Keywords

Animals, Urinary Bladder Neoplasms, Pyridones, Pyrimidinones, Rosiglitazone, Mice, Disease Models, Animal, Apoptosis, Humans, Cell Proliferation, Cell Line, Tumor, Antineoplastic Agents, Neoplasm Invasiveness, Female, PPAR gamma, Thiazolidinediones, Cell Differentiation, Signal Transduction, Retinoids

Comments

Supplementary Materials

Data Availability Statement

PMID: 39095358