RAF1 amplification: an exemplar of MAPK pathway activation in urothelial carcinoma

Abstract

Despite recent therapeutic gains in the treatment of advanced bladder cancer, the overall survival in patients with metastatic disease remains poor and further therapeutic discovery is needed. Advanced bladder cancer is a molecularly heterogeneous disease, and the identification of driver genetic alterations has led to effective targeted therapeutic agents, such as fibroblast growth factor receptor (FGFR) inhibitors. In this issue of the JCI, Bekele et al. identify a subtype of muscle-invasive bladder cancer (MIBC) that harbors RAF1 amplification. The authors showed that RAF1 inhibition, with pan-RAF inhibitors, and the combination of RAF1 inhibition with MEK inhibition were efficacious in preclinical models harboring RAF1 amplifications as well as in tumors with HRAS and NRAS mutations. This study highlights RAF1 amplification as a driver event in bladder cancer and establishes the central role of the MAPK pathway in bladder tumorigenesis.

Figure 1. MAPK activation and targeting in bladder cancer.

(A) The RAF/MEK/ERK signaling cascade links extracellular signals to cell differentiation, proliferation, and growth. (B) The Cancer Genome Atlas (TCGA) indicates that MAPK alterations make up 36.4 % of high-grade MIBCs. (C) Specific inhibitors may differentially target putative genomic alterations that activate the MAPK pathway to treat bladder tumors. Asterisks indicate mutations.