Ponatinib Inhibits Multiple Signaling Pathways Involved in STAT3 Signaling and Attenuates Colorectal Tumor Growth

Abstract : Signal transducer and activator of transcription 3 (STAT3) signaling is a major driver of colorectal cancer (CRC) growth, however therapeutics, which can effectively target this pathway, have so far remained elusive. Here, we performed an extensive screen for STAT3 inhibitors among a library of 1167 FDA-approved agents, identifying Ponatinib as a lead candidate. We found that Ponatinib inhibits STAT3 activity driven by EGF/EGFR, IL-6/IL-6R and IL-11/IL-11R, three major ligand/receptor systems involved in CRC development and progression. Ponatinib was able to inhibit CRC migration and tumor growth in vivo. In addition, Ponatinib displayed a greater ability to inhibit STAT3 activity and mediated superior anti-proliferative efficacy compared to five FDA approved SRC and Janus Kinase (JAK) inhibitors. Finally, long-term exposure of CRC cells to Ponatinib, Dasatinib and Bosutinib resulted in acquired resistance to Dasatinib and Bosutinib occurring within six weeks. However, acquired resistance to Ponatinib was observed after long-term exposure of >4 months. Overall, our results identify a novel anti-STAT3 property of Ponatinib and thus, Ponatinib offers a potential therapeutic strategy for CRC.
Type de document :
Article dans une revue
Liste complète des métadonnées

https://hal.umontpellier.fr/hal-02073214
Contributeur : Cécile Nowak <>
Soumis le : mardi 19 mars 2019 - 16:32:47
Dernière modification le : mercredi 14 août 2019 - 16:02:05

Lien texte intégral

Identifiants

Collections

Citation

F. H. Tan, T. L. Putoczki, J. Lou, E. Hinde, Frédéric Hollande, et al.. Ponatinib Inhibits Multiple Signaling Pathways Involved in STAT3 Signaling and Attenuates Colorectal Tumor Growth. Cancers, MDPI, 2018, 10 (12), ⟨10.3390/cancers10120526⟩. ⟨hal-02073214⟩

Partager

Métriques

Consultations de la notice

35