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

Chandra Sekhar Amara, Karthik Reddy Kami Reddy, Yang Yuntao, Yuen San Chan, Danthasinghe Waduge Badrajee Piyarathna, Lacey Elizabeth Dobrolecki, David J. H. Shih, Zhongcheng Shi, Jun Xu, Shixia Huang, Matthew J. Ellis, Andrea B. Apolo, Leomar Y. Ballester, Jianjun Gao, Donna E. Hansel, Yair Lotan, H. Courtney Hodges, Seth P. Lerner, Chad J. Creighton, Arun Sreekumar, W. Jim Zheng, Pavlos Msaouel (), Shyam M. Kavuri () and Nagireddy Putluri ()
Additional contact information
Chandra Sekhar Amara: Baylor College of Medicine
Karthik Reddy Kami Reddy: Baylor College of Medicine
Yang Yuntao: University of Texas Health Science Center at Houston
Yuen San Chan: Baylor College of Medicine
Danthasinghe Waduge Badrajee Piyarathna: Baylor College of Medicine
Lacey Elizabeth Dobrolecki: Baylor College of Medicine
David J. H. Shih: University of Texas Health Science Center at Houston
Zhongcheng Shi: Baylor College of Medicine
Jun Xu: Baylor College of Medicine
Shixia Huang: Baylor College of Medicine
Matthew J. Ellis: Baylor College of Medicine
Andrea B. Apolo: Center for Cancer Research, National Cancer Institute, National Institutes of Health
Leomar Y. Ballester: The University of Texas MD Anderson Cancer Center
Jianjun Gao: The University of Texas MD Anderson Cancer Center
Donna E. Hansel: The University of Texas MD Anderson Cancer Center
Yair Lotan: University of Texas Southwestern Medical Center
H. Courtney Hodges: Baylor College of Medicine
Seth P. Lerner: Baylor College of Medicine
Chad J. Creighton: Baylor College of Medicine
Arun Sreekumar: Baylor College of Medicine
W. Jim Zheng: University of Texas Health Science Center at Houston
Pavlos Msaouel: Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center
Shyam M. Kavuri: Baylor College of Medicine
Nagireddy Putluri: Baylor College of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract SMARCB1 loss has long been observed in many solid tumors. However, there is a need to elucidate targetable pathways driving growth and metastasis in SMARCB1-deficient tumors. Here, we demonstrate that SMARCB1 deficiency, defined as genomic SMARCB1 copy number loss associated with reduced mRNA, drives disease progression in patients with bladder cancer by engaging STAT3. SMARCB1 loss increases the chromatin accessibility of the STAT3 locus in vitro. Orthotopically implanted SMARCB1 knockout (KO) cell lines exhibit increased tumor growth and metastasis. SMARCB1-deficient tumors show an increased IL6/JAK/STAT3 signaling axis in in vivo models and patients. Furthermore, a pSTAT3 selective inhibitor, TTI-101, reduces tumor growth in SMARCB1 KO orthotopic cell line-derived xenografts and a SMARCB1-deficient patient derived xenograft model. We have identified a gene signature generated from SMARCB1 KO tumors that predicts SMARCB1 deficiency in patients. Overall, these findings support the clinical evaluation of STAT3 inhibitors for the treatment of SMARCB1-deficient bladder cancer.

Date: 2024
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DOI: 10.1038/s41467-024-45132-2

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