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Updated: Oct 19, 2025

Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
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RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics

Raie T Bekele1,2, Amruta S Samant1, Amin H Nassar3,4

  • 1Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.

The Journal of Clinical Investigation
|September 23, 2021
PubMed

Insights

Researchers discovered that nearly 20% of urothelial tumors depend on the RAF1 (CRAF) kinase gene. Targeting this RAF1-mediated signaling offers a promising new therapeutic strategy for bladder cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Bladder cancer is a complex genetic disease requiring new treatments.
  • Current therapies have limitations, necessitating novel approaches.

Purpose of the Study:

  • To identify novel therapeutic targets in urothelial tumors.
  • To investigate the role of RAF1 kinase in bladder cancer development and treatment.

Main Methods:

  • Genomic analysis to identify gene amplifications in urothelial tumors.
  • Functional studies using cell lines and patient-derived models.
  • Assessment of sensitivity to RAF and MEK inhibitors.

Main Results:

  • A subset of urothelial tumors exhibits focal amplification of the RAF1 (CRAF) gene.
  • RAF1-amplified tumors show activation of the RAF/MEK/ERK pathway and a luminal gene expression pattern.
  • These tumors are dependent on RAF1 activity and sensitive to RAF inhibitors, including combination therapy with MEK inhibitors.
  • Bladder tumors with HRAS/NRAS mutations also rely on RAF1 signaling and respond to RAF1-targeted therapy.

Conclusions:

  • RAF1 activation is a critical dependency in approximately 20% of urothelial tumors.
  • Targeting RAF1-mediated signaling is a rational and potentially effective therapeutic strategy for a significant subset of bladder cancer patients.
  • This finding opens new avenues for precision medicine in bladder cancer treatment.
Keywords:
CancerDrug therapyOncogenesOncology

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