TWIST1 is a critical downstream target of the HGF/MET pathway and is required for MET driven acquired resistance in oncogene driven lung cancer
© 2024. The Author(s)..
MET amplification/mutations are important targetable oncogenic drivers in NSCLC, however, acquired resistance is inevitable and the majority of patients with targetable MET alterations fail to respond to MET tyrosine kinase inhibitors (TKIs). Furthermore, MET amplification is among the most common mediators of TKI resistance. As such, novel therapies to target MET pathway and overcome MET TKI resistance are clearly needed. Here we show that the epithelial-mesenchymal transition (EMT) transcription factor, TWIST1 is a key downstream mediator of HGF/MET induced resistance through suppression of p27 and targeting TWIST1 can overcome resistance. We found that TWIST1 is overexpressed at the time of TKI resistance in multiple MET-dependent TKI acquired resistance PDX models. We have shown for the first time that MET directly stabilized the TWIST protein leading to TKI resistance and that TWIST1 was required for MET-driven lung tumorigenesis as well as could induce MET TKI resistance when overexpressed. TWIST1 mediated MET TKI resistance through suppression of p27 expression and genetic or pharmacologic inhibition of TWIST1 overcame TKI resistance in vitro and in vivo. Our findings suggest that targeting TWIST1 may be an effective therapeutic strategy to overcome resistance in MET-driven NSCLC as well as in other oncogene driven subtypes in which MET amplification is the resistance mechanism.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Oncogene - (2024) vom: 01. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kumar, Vinod [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 18.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1038/s41388-024-02987-5 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369754247 |
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| 100 | 1 | |a Kumar, Vinod |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a TWIST1 is a critical downstream target of the HGF/MET pathway and is required for MET driven acquired resistance in oncogene driven lung cancer |
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| 520 | |a © 2024. The Author(s). | ||
| 520 | |a MET amplification/mutations are important targetable oncogenic drivers in NSCLC, however, acquired resistance is inevitable and the majority of patients with targetable MET alterations fail to respond to MET tyrosine kinase inhibitors (TKIs). Furthermore, MET amplification is among the most common mediators of TKI resistance. As such, novel therapies to target MET pathway and overcome MET TKI resistance are clearly needed. Here we show that the epithelial-mesenchymal transition (EMT) transcription factor, TWIST1 is a key downstream mediator of HGF/MET induced resistance through suppression of p27 and targeting TWIST1 can overcome resistance. We found that TWIST1 is overexpressed at the time of TKI resistance in multiple MET-dependent TKI acquired resistance PDX models. We have shown for the first time that MET directly stabilized the TWIST protein leading to TKI resistance and that TWIST1 was required for MET-driven lung tumorigenesis as well as could induce MET TKI resistance when overexpressed. TWIST1 mediated MET TKI resistance through suppression of p27 expression and genetic or pharmacologic inhibition of TWIST1 overcame TKI resistance in vitro and in vivo. Our findings suggest that targeting TWIST1 may be an effective therapeutic strategy to overcome resistance in MET-driven NSCLC as well as in other oncogene driven subtypes in which MET amplification is the resistance mechanism | ||
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| 700 | 1 | |a Yochum, Zachary A |e verfasserin |4 aut | |
| 700 | 1 | |a Devadassan, Princey |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Eric H-B |e verfasserin |4 aut | |
| 700 | 1 | |a Miller, Ethan |e verfasserin |4 aut | |
| 700 | 1 | |a Baruwal, Roja |e verfasserin |4 aut | |
| 700 | 1 | |a Rumde, Purva H |e verfasserin |4 aut | |
| 700 | 1 | |a GaitherDavis, Autumn L |e verfasserin |4 aut | |
| 700 | 1 | |a Stabile, Laura P |e verfasserin |4 aut | |
| 700 | 1 | |a Burns, Timothy F |e verfasserin |4 aut | |
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