The IL6/Jak/STAT3 Signaling Axis Is a Therapeutic Vulnerability in SMARCB1-Deficient Bladder Cancer

Authors

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
Nagireddy Putluri

Publication Date

2-14-2024

Journal

Nature Communications

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.

Keywords

Humans, Interleukin-6, Signal Transduction, SMARCB1 Protein, Urinary Bladder Neoplasms, Cell Line, Tumor, STAT3 Transcription Factor

Comments

Supplementary Materials

PMID: 38355560