Rosiglitazone and trametinib exhibit potent anti-tumor activity in a mouse model of muscle invasive bladder cancer

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 and Cathy Lee Mendelsohn ()
Additional contact information
Sakina A. Plumber: Columbia University Irving Medical Center
Tiffany Tate: Columbia University Irving Medical Center
Hikmat Al-Ahmadie: Memorial Sloan Kettering Cancer Center
Xiao Chen: Columbia University Irving Medical Center
Woonyoung Choi: Johns Hopkins Greenberg Bladder Cancer Institute
Merve Basar: Columbia University Irving Medical Center
Chao Lu: Columbia University Irving Medical Center
Aaron Viny: Columbia University Irving Medical Center
Ekatherina Batourina: Columbia University Irving Medical Center
Jiaqi Li: Columbia University Irving Medical Center
Kristjan Gretarsson: Columbia University Irving Medical Center
Besmira Alija: Columbia University Irving Medical Center
Andrei Molotkov: Columbia University Irving Medical Center
Gregory Wiessner: Columbia University Irving Medical Center
Byron Hing Lung Lee: The University of Texas MD Anderson Cancer Center
James McKiernan: Columbia University Irving Medical Center
David J. McConkey: Johns Hopkins Greenberg Bladder Cancer Institute
Colin Dinney: The University of Texas MD Anderson Cancer Center
Bogdan Czerniak: The University of Texas MD Anderson Cancer Center
Cathy Lee Mendelsohn: Columbia University Irving Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50678-2

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