RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics
Raie T. Bekele, … , Eliezer M. Van Allen, Kent W. Mouw
Raie T. Bekele, … , Eliezer M. Van Allen, Kent W. Mouw
Published September 23, 2021
Citation Information: J Clin Invest. 2021;131(22):e147849. https://doi.org/10.1172/JCI147849.
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RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics

Abstract

Bladder cancer is a genetically heterogeneous disease, and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here, we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient-derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS- or NRAS-activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a dependency in a subset making up nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rational therapeutic strategy.

Authors

Raie T. Bekele, Amruta S. Samant, Amin H. Nassar, Jonathan So, Elizabeth P. Garcia, Catherine R. Curran, Justin H. Hwang, David L. Mayhew, Anwesha Nag, Aaron R. Thorner, Judit Börcsök, Zsofia Sztupinszki, Chong-Xian Pan, Joaquim Bellmunt, David J. Kwiatkowski, Guru P. Sonpavde, Eliezer M. Van Allen, Kent W. Mouw

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Figure 5

RAF1-amplified tumors are sensitive to RAF and MEK inhibition in vivo.

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RAF1-amplified tumors are sensitive to RAF and MEK inhibition in vivo. ...
(A) Tumor volumes of UMUC9-engrafted mice treated twice weekly with PEG400 vehicle (n = 9 mice), PEG400 with 4% DMSO vehicle (n = 5), RAF265 (n = 10), or RAF265 plus trametinib (n = 8). The black arrow denotes the day of first treatment. Significant differences in average tumor size are denoted by asterisks. **P < 0.005; ***P < 0.0005, ANOVA with Bonferroni’s post hoc test. (B) Mice treated with RAF265 alone or with RAF265 plus trametinib had significantly lower end-of-experiment tumor weights than vehicle-treated mice. Significant differences were calculated by ANOVA with Bonferroni’s post hoc test and are denoted by asterisks. *P < 0.05; **P < 0.005; ***P < 0.0005. (C) Photographs of excised tumors across treatment arms. (D) FISH assay showing RAF1 amplification (red) in UMUC9 tumor xenografts. CEP3 (green) is a chromosome 3 centromeric marker.