RAF1 amplification: an exemplar of MAPK pathway activation in urothelial carcinoma
Sean Clark-Garvey1 and William Y. Kim1,2,3,4
1Division of Oncology, Department of Medicine;
2Lineberger Comprehensive Cancer Center;
3Department of Pharmacology; and
4 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Address correspondence to: William Y. Kim, Lineberger Comprehensive Cancer Center, University of North Carolina, CB# 7295, Chapel Hill, North Carolina 27599-7295, USA. Phone: 919.966.4765; Email: wykim@med.unc.edu.
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1Division of Oncology, Department of Medicine;
2Lineberger Comprehensive Cancer Center;
3Department of Pharmacology; and
4 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Address correspondence to: William Y. Kim, Lineberger Comprehensive Cancer Center, University of North Carolina, CB# 7295, Chapel Hill, North Carolina 27599-7295, USA. Phone: 919.966.4765; Email: wykim@med.unc.edu.
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Kim, W.
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Published November 15, 2021 - More info
J Clin Invest. 2021;131(22):e154095. https://doi.org/10.1172/JCI154095.
© 2021 American Society for Clinical Investigation
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.
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