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, Cathy Lee, Mendelsohn

Nature Communications |

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.