Repurposing ponatinib for the treatment of colorectal cancer
Authors: F. Tan, T. Putoczki, F. Hollande, R. Luwor
Journal: Annals of Oncology (2018)

Introduction: Colorectal cancer (CRC) is the 4th most common cancer globally. Despite, targeted agents producing advances in some CRC patients, tumour progression is still frequently observed. Further research is urgently needed to realise the potential of targeted therapies for CRC. A key transcription factor to potentially target is Signal Transducer and Activator of Transcription 3 (STAT3). In over 50% of human CRC tissue, STAT3 is hyper-activated, and considerable evidence demonstrates that STAT3 is critical for CRC progression. Inhibiting STAT3 is therefore a crucial step in advancing CRC treatment. But the matter is complicated by the fact that key receptors such as the Epidermal growth factor receptor (EGFR), Interleukin-6 receptor (IL-6R), and Interleukin-11 receptor (IL-11R) all activate STAT3. We and others have shown that blocking one receptor is not sufficient in inhibiting STAT3 activity, as other uninhibited pathways can reactivate STAT3, leading to continued tumour growth and refractory outcomes clinically. Therefore, identifying a therapeutic agent that can inhibit STAT3 activity driven by several upstream mediators, including EGFR, IL-6R and IL-11R, is required to reduce compensatory signalling and STAT3 reactivation. As it stands, the discovery of such a therapeutic agent has not been achieved. Methods: Here we perform a luciferase based screen on a panel of approximately 1200 FDA approved agents to identify inhibitors that can block EGF, IL-6 and IL-11 mediated STAT3 activity. Following a secondary western blot screen, we identified ponatinib as a candidate anti-STAT3 inhibitor. We further validated our results and characterised ponatinib's anti-STAT3 properties using RT-PCR, cell viability, cell migration and animal xenograft models. Results: Here, we describe an extensive screen for an anti-STAT3 inhibitor from 1167 FDA-approved agents, identifying ponatinib as a lead candidate. Importantly, ponatinib could inhibit STAT3 activity and downstream transcriptional regulation driven from EGF, IL-6 and IL-11, 3 major ligands involved in CRC development and progression. Ponatinib also produced significant inhibition of CRC migration and in vivo tumour growth. Furthermore, ponatinib, displayed superior STAT3 inhibition and anti-proliferative efficacy compared to 5 FDA approved SRC and JAK inhibitors. Finally, long-term exposure of CRC cells resulted in acquired resistance to SRC and JAK inhibitors within 6 weeks, while acquired resistance to ponatinib was only observed after long-term exposure of > 4 months. These results identify ponatinib as a broad STAT3 inhibitor that offers a potential therapeutic strategy for CRC and other tumour types. Conclusion: In summary, we successfully identified a novel mechanism for the currently FDA-approved agent ponatinib with inhibitory properties against STAT3 activity in CRC. Overall, our findings provide proof-of-principle evidence for the re-purposing of ponatinib into the clinical management of CRC patients with tumours harbouring elevated STAT3 activity driven by related growth factors and cytokines.