Ponatinib inhibits multiple signaling pathways involved in STAT3 signaling and attenuates colorectal tumor growth
Details
Publication Year 2018-12-19, Volume 10, Issue #12, Page E526
Journal Title
Cancers
Publication Type
Journal Article
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.
Publisher
MDPI
WEHI Research Division(s)
Inflammation; Systems Biology And Personalised Medicine
PubMed ID
30572654
Open Access at Publisher's Site
https://doi.org/10.3390/cancers10120526
NHMRC Grants
NHMRC/1080498 NHMRC/1136119 NHMRC/1079362
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2019-01-15 09:07:43
Last Modified: 2019-01-15 09:27:16
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