Anti-tumor effect of trametinib in bladder cancer organoid and the
underlying mechanism
Abstract
Bladder cancer (BC), a main neoplasm of urinary tract, is usually
inoperable and unresponsive to chemotherapy, indicating a necessity for
more effective therapies. As a novel experimental model for
muscle-invasive BC, we previously established a culture method of dog BC
organoids. In the present study, the detailed in vitro and in vivo
anti‐tumor effects of trametinib were investigated by using this model.
In each BC organoid strain, epidermal growth factor receptor (EGFR)/ERK
signaling was upregulated compared with normal bladder cells. Trametinib
even at a low concentration inhibited the cell viability of BC organoids
and the activation of ERK through decreasing expression of c-Myc, ELK1,
SIK1, and PLA2G4A. Trametinib arrested cell cycle of BC with few
apoptoses. Additionally, trametinib decreased expression of CD44, while
YAP1 was unexpectedly upregulated. Dual treatment of BC organoids with
trametinib and YAP inhibitor, verteporfin extremely inhibited the cell
viability with apoptosis induction. Moreover, trametinib induced basal
to luminal transformation of BC organoids by upregulating luminal
markers (ERBB2 and GATA3) and downregulating basal ones (CK5 and DSG3).
In vivo, trametinib decreased the tumor growth of BC organoids in mice
and the xenograft-derived organoids from trametinib-administered mice
showed enhanced sensitivity to carboplatin due to MSH2 upregulation. Our
data suggested a new strategy of trametinib-YAP inhibitor or
trametinib-carboplatin combination as a promising treatment of BC. Dog
BC organoid model may hopefully become a promising research tool for
human muscle-invasive BC in near future.