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.
Nature communications. 2024 Feb 14*** epublish ***
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
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA., Mcwilliams School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Advanced Technology Cores, Baylor College of Medicine, Houston, TX, 77030, USA., Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA., Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA., Scott Department of Urology, Baylor College of Medicine, Houston, TX, 77030, USA., Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA., Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. ., Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA. ., Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. .