Abstract 929: A novel STAT3 inhibitor directly targeting STAT3 N-terminus simultaneously abrogates the nuclear and mitochondrial STAT3 activities leading to highly potent anti-cancer efficacy on the breast cancer

Abstract

Abstract STAT3 functions are largely bifurcated: (1) STAT3 activated by Y705 phosphorylation (pY705) regulates target-gene expression in nucleus. (2) STAT3 activated by S727 phosphorylation (pS727) supports a electron transport complex (ETC) in mitochondria. Constitutive activation of STAT3 has long been considered to correlate with activation of diverse oncogenic pathways, which is a promising target for anti-cancer agents, but clinical therapeutic options are still unsatisfactory. Here we discovered a highly novel small-molecule inhibitor, JW-STAT3i directly binding to STAT3 N-terminal domain: 1) Through the cancer cell line panel screening, JW-STAT3i shows strong anti-cancer potency on various cancer cell lines including the breast cancer cell lines. 2) Anti-cancer mechanism of JW-STAT3i was elucidated: Firstly, the JW-STAT3i impairs pY705-STAT3 to abrogate pro-tumorigenic transcriptional programs mediated by STAT3. Secondly, JW-STAT3i also blocks pS727-STAT3 leading to mitochondrial dysfunction and AMPK activation. Consequently, JW-STAT3i treated cancer cells undergo growth arrest and apoptosis. 3) We further validated JW-STAT3i efficacy using cancer cell line- and patient-derived xenograft models whose response is well-correlated with the predictive biomarkers identified. Accuracy of in vivo efficacy in selected breast cancer PDX models based on predictive biomarker (estimated responders and non-responders) was very high. 4) We also demonstrated that JW-STAT3i shows a strong synergy with anti-PD-L1 antibody by induction of anti-tumorigenic immune environment. In conclusion, JW-STAT3i possesses both negative and positive effects on cancer cell proliferation and anti-immunity respectively. Currently, JW-STAT3i is under preclinical development and highly expected to be a promising anticancer therapeutic option in the near future. Citation Format: Jinsuk Kang. A novel STAT3 inhibitor directly targeting STAT3 N-terminus simultaneously abrogates the nuclear and mitochondrial STAT3 activities leading to highly potent anti-cancer efficacy on the breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 929.