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 novel dependency in a subset comprising nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rationale therapeutic strategy.
The Journal of clinical investigation. 2021 Sep 23 [Epub ahead of print]
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
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, United States of America., Department of Medicine, Brigham & Women's Hospital, Boston, United States of America., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America., Department of Pathology, Brigham & Women's Hospital, Boston, United States of America., Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, United States of America., Danish Cancer Society Research Center, Copenhagen, Denmark., Translational Cancer Genomics, Danish Cancer Society Research Center, Copenhagen, Denmark., Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, United States of America.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/34554931
Read an Expert Commentary by Bishoy Faltas, MD