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; Nagireddy Putluri

doi:10.1038/s41467-024-45132-2

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 SreekumarW. Jim Zheng, Pavlos Msaouel, Shyam M. Kavuri, Nagireddy Putluri

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	1373
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-45132-2
State	Published - Dec 2024

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Amara, C. S., Kami Reddy, K. R., Yuntao, Y., Chan, Y. S., Piyarathna, D. W. B., Dobrolecki, L. E., Shih, D. J. H., Shi, Z., Xu, J., Huang, S., Ellis, M. J., Apolo, A. B., Ballester, L. Y., Gao, J., Hansel, D. E., Lotan, Y., Hodges, H. C., Lerner, S. P., Creighton, C. J., ... Putluri, N. (2024). The IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer. Nature communications, 15(1), Article 1373. https://doi.org/10.1038/s41467-024-45132-2

Amara, CS, Kami Reddy, KR, Yuntao, Y, Chan, YS, Piyarathna, DWB, Dobrolecki, LE, Shih, DJH, Shi, Z, Xu, J, Huang, S, Ellis, MJ, Apolo, AB, Ballester, LY , Gao, J , Hansel, DE, Lotan, Y, Hodges, HC, Lerner, SP, Creighton, CJ, Sreekumar, A, Zheng, WJ, Msaouel, P, Kavuri, SM & Putluri, N 2024, 'The IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer', Nature communications, vol. 15, no. 1, 1373. https://doi.org/10.1038/s41467-024-45132-2

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

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.",

author = "Amara, {Chandra Sekhar} and {Kami Reddy}, {Karthik Reddy} and Yang Yuntao and Chan, {Yuen San} and Piyarathna, {Danthasinghe Waduge Badrajee} and Dobrolecki, {Lacey Elizabeth} and Shih, {David J.H.} and Zhongcheng Shi and Jun Xu and Shixia Huang and Ellis, {Matthew J.} and Apolo, {Andrea B.} and Ballester, {Leomar Y.} and Jianjun Gao and Hansel, {Donna E.} and Yair Lotan and Hodges, {H. Courtney} and Lerner, {Seth P.} and Creighton, {Chad J.} and Arun Sreekumar and Zheng, {W. Jim} and Pavlos Msaouel and Kavuri, {Shyam M.} and Nagireddy Putluri",

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doi = "10.1038/s41467-024-45132-2",

language = "English (US)",

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AU - Amara, Chandra Sekhar

AU - Kami Reddy, Karthik Reddy

AU - Yuntao, Yang

AU - Chan, Yuen San

AU - Piyarathna, Danthasinghe Waduge Badrajee

AU - Dobrolecki, Lacey Elizabeth

AU - Shih, David J.H.

AU - Shi, Zhongcheng

AU - Xu, Jun

AU - Huang, Shixia

AU - Ellis, Matthew J.

AU - Apolo, Andrea B.

AU - Ballester, Leomar Y.

AU - Gao, Jianjun

AU - Hansel, Donna E.

AU - Lotan, Yair

AU - Hodges, H. Courtney

AU - Lerner, Seth P.

AU - Creighton, Chad J.

AU - Sreekumar, Arun

AU - Zheng, W. Jim

AU - Msaouel, Pavlos

AU - Kavuri, Shyam M.

AU - Putluri, Nagireddy

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

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

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