| Literature DB >> 34554931 |
Raie T Bekele1,2, Amruta S Samant1, Amin H Nassar3,4, Jonathan So4, Elizabeth P Garcia3, Catherine R Curran4, Justin H Hwang2,4, David L Mayhew2,4, Anwesha Nag5, Aaron R Thorner5, Judit Börcsök6, Zsofia Sztupinszki6, Chong-Xian Pan7, Joaquim Bellmunt8, David J Kwiatkowski2,3, Guru P Sonpavde4, Eliezer M Van Allen2,4, Kent W Mouw1,2,3.
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.Entities:
Keywords: Cancer; Drug therapy; Oncogenes; Oncology
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Year: 2021 PMID： 34554931 PMCID： PMC8592548 DOI： 10.1172/JCI147849
Source DB: PubMed Journal: J Clin Invest ISSN： 0021-9738 Impact factor: 19.456