The IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer
© 2024. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
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| Enthalten in: |
Nature communications - 15(2024), 1 vom: 14. Feb., Seite 1373 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Amara, Chandra Sekhar [VerfasserIn] |
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| Links: |
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| Themen: |
Interleukin-6 |
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| Anmerkungen: |
Date Completed 16.02.2024 Date Revised 17.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-024-45132-2 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368456641 |
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| 100 | 1 | |a Amara, Chandra Sekhar |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a 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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| 700 | 1 | |a Yuntao, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Yuen San |e verfasserin |4 aut | |
| 700 | 1 | |a Piyarathna, Danthasinghe Waduge Badrajee |e verfasserin |4 aut | |
| 700 | 1 | |a Dobrolecki, Lacey Elizabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Shih, David J H |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Zhongcheng |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Jun |e verfasserin |4 aut | |
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| 700 | 1 | |a Apolo, Andrea B |e verfasserin |4 aut | |
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