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Merck

RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics.

The Journal of clinical investigation (2021-09-24)
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
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.

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Sigma-Aldrich
Anti-RAF1 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution