Valentine, HE; (2017) Characterisation of a novel STAT3 inhibitor, VS-43, and the role of STAT3 in the repair of DNA-interstrand crosslinks. Doctoral thesis , UCL (University College London).

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Abstract

Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor constitutively activated in cancer, leading to survival, proliferation, angiogenesis and metastasis. STAT3 inhibitors possess anti-cancer properties, however, the selectivity and potency of current inhibitors must be improved. This thesis characterises a novel STAT3 inhibitor, VS-43. VS-43 is a potent and selective STAT3 inhibitor, able to inhibit cancer cell growth and induce apoptosis in cancer cell lines. VS-43 is shown to inhibit STAT3 DNA binding and downstream target expression. VS-43 is also able to synergise with cisplatin, and this combination is more synergistic than the combination of cisplatin with other STAT3 inhibitors. Cisplatin acts via the formation of adducts with the cellular DNA, and the interstrand crosslink (ICL) is the most toxic of the cisplatin lesions. Resistance to cisplatin can occur via enhanced repair of ICLs. Therefore, the effect of STAT3 inhibition on ICL repair was investigated. STAT3 nhibitors are shown to block the unhooking of cisplatin-induced ICLs and down-regulate the expression of the ICL repair factors EME1, MUS81, BRCA1 and FANCD2. Binding of STAT3 to the MUS81 and EME1 promoters was demonstrated using ChIP assays, suggesting direct transcriptional regulation of the MUS81-EME1 nuclease by STAT3. In contrast, STAT3 inhibitors did not synergise with melphalan and did not block melphalan-ICL unhooking. siRNA knockdown of MUS81 or EME1 demonstrated that the MUS81-EME1 nuclease is selectively involved in cisplatin-ICL repair. This thesis presents VS-43 as a promising novel STAT3 inhibitor, and provides mechanistic insight into how STAT3 inhibitors synergise with cisplatin through the regulation of ICL unhooking. Understanding the differences in the repair of different ICLs will be essential for the design of future chemotherapy combinations.

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