Ponatinib inhibits STAT3 activity and reduces colorectal cancer growth
Document TypePhD thesis
Access StatusOpen Access
© 2017 Dr Fiona Tan
Colorectal cancer is the 4th most common cancer globally and the 2nd most common cancer in Australia. Constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been observed in over 50% of human colorectal carcinomas and its role in tumour progression has been confirmed in numerous mouse models and clinically in human samples. Previous data suggests the hyper-activation of upstream molecules notably, Epidermal Growth Factor Receptor (EGFR) and the Interleukin (IL)-6-gp130 family of cytokines, contributes to enhanced STAT3 activation and tumourigenesis . With the aim of overcoming STAT3-driven tumourigenicity, we evaluated a panel of 1167 FDA approved agents for their ability to inhibit STAT3 activity. In this initial drug screen, human colorectal cancer cell lines were assessed by the adenoviral STAT3 luciferase reporter assay. In the presence of inhibitors, cells were also stimulated with EGF and IL-6 allowing enhanced STAT3 activity at 10µM. We identified 51 FDA approved agents to have reduced STAT3 activity by ≥50%. Our secondary drug screen further evaluated inhibitors by EGF and IL-6 mediated STAT3 activity by western blot and resulted with 9 inhibitors to have shown successive reduction at 1µM. It has been recently shown that IL-11, a closely related IL-6 family member has a more prominent role than IL-6 during the progression of gastrointestinal cancers, including colorectal tumours , and therefore in our tertiary screen we further evaluated agents that could inhibit IL-11, IL-6 and EGF mediated STAT3 phosphorylation by western blot analyses. As a result, Ponatinib (AP24534) markedly reduced EGF, IL-6 and IL-11 driven STAT3 activation. Ponatinib is a multi-targeted tyrosine kinase inhibitor and is currently approved for the treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. With further in-vitro and in-vivo analyses performed, Ponatinib also reduced transcriptional gene expression of STAT3 regulated genes (SOCS3), cell viability, migration and tumour growth. In addition, Ponatinib was also observed to reduce LIF (another member of the IL-6 family of cytokines) driven STAT3 activity. This study demonstrated Ponatinib’s preferentially targets the IL-11 driven STAT3 pathway in CRC cell lines when compared to IL-11 driven AKT and ERK1/2 signalling pathways. We therefore, further explored the possibility of Ponatinib to directly target IL-11R/gp130 and speculate possible interaction however, further analysis is required to determine this theory. While the effectiveness of Ponatinib requires additional investigation, our findings both in-vitro and in-vivo offer proof-of-principle evidence for the potential use of Ponatinib for the treatment of STAT3 driven colorectal cancers.
KeywordsColorectal cancer, STAT3, Cancer, Signal Transduction
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