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The IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer

Chandra Sekhar Amara1, Karthik Reddy Kami Reddy1,2, Yang Yuntao3

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.

Nature Communications
|February 14, 2024
PubMed

Insights

SMARCB1 loss in bladder cancer promotes tumor growth and metastasis by activating the STAT3 pathway. Targeting STAT3 with inhibitors like TTI-101 shows promise for treating these aggressive tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • SMARCB1 loss is prevalent in various solid tumors, necessitating the identification of actionable pathways.
  • Understanding the mechanisms driving tumor progression in SMARCB1-deficient cancers is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the role of SMARCB1 deficiency in bladder cancer progression.
  • To identify and validate targetable pathways, specifically focusing on STAT3, in SMARCB1-deficient bladder tumors.

Main Methods:

  • Utilized SMARCB1 knockout (KO) cell lines and orthotopic implantation models in vivo.
  • Analyzed chromatin accessibility, IL6/JAK/STAT3 signaling, and gene expression signatures.
  • Evaluated the efficacy of the STAT3 inhibitor TTI-101 in preclinical models.

Main Results:

  • SMARCB1 deficiency drives bladder cancer progression and metastasis by enhancing STAT3 signaling.
  • SMARCB1 loss increases chromatin accessibility at the STAT3 locus.
  • TTI-101 treatment significantly reduced tumor growth in preclinical models.
  • A novel gene signature was identified to predict SMARCB1 deficiency.

Conclusions:

  • SMARCB1 deficiency engages the IL6/JAK/STAT3 pathway, promoting bladder cancer growth and metastasis.
  • STAT3 inhibition represents a potential therapeutic strategy for SMARCB1-deficient bladder cancer.
  • The identified gene signature can aid in patient stratification for targeted therapies.

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