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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 131 Issue 22 (11 15 2021) ISSN: 1558-8238 [Electronic] United States
• PMID: 34554931 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-raf
• Raf1 protein, human
• Mitogen-Activated Protein Kinase Kinases
• GTP Phosphohydrolases
• NRAS protein, human
• HRAS protein, human
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Cell Line, Tumor
• Female
• GTP Phosphohydrolases (genetics)
• Gene Amplification
• Humans
• Membrane Proteins (genetics)
• Mice
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Protein Kinase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins c-raf (antagonists & inhibitors, genetics)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Urinary Bladder Neoplasms (drug therapy, genetics)