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Open AccessArticle

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

1
Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville VIC 3050, Australia
2
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville VIC 3052, Australia
3
Department of Medical Biology, The University of Melbourne, Parkville VIC 3050, Australia
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Department of Biochemistry and Molecular Biology, Bio21, The University of Melbourne, Parkville VIC 3010, Australia
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Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, Melbourne VIC 3000, Australia
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CNRS, Institut de Génomique Fonctionnelle, Universités de Montpellier 1 & 2, UMR-5203, INSERM U661, 34094 Montpellier, France
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Department of Neurosurgery, The Royal Melbourne Hospital, Parkville VIC 3050, Australia
8
Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville VIC 3052, Australia
9
School of Biomedical Sciences, Monash University, Clayton VIC 3168, Australia
*
Author to whom correspondence should be addressed.
Cancers 2018, 10(12), 526; https://doi.org/10.3390/cancers10120526
Received: 5 December 2018 / Accepted: 14 December 2018 / Published: 19 December 2018
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. View Full-Text
Keywords: STAT3; CRC; Ponatinib; EGFR; interleukin signaling STAT3; CRC; Ponatinib; EGFR; interleukin signaling
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Tan, F.H.; Putoczki, T.L.; Lou, J.; Hinde, E.; Hollande, F.; Giraud, J.; Stylli, S.S.; Paradiso, L.; Zhu, H.-J.; Sieber, O.M.; Luwor, R.B. Ponatinib Inhibits Multiple Signaling Pathways Involved in STAT3 Signaling and Attenuates Colorectal Tumor Growth. Cancers 2018, 10, 526.

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