Abstract 1459: PTP4A3 phosphatase is a novel drug target for epithelial ovarian cancer

Abstract

Abstract High grade serous ovarian cancer (HGSOC) is the deadliest epithelial ovarian cancer (EOC) variant, with a bleak outcome that kills >14,000 women annually in the US. In past four decades, first line therapies have changed only modestly. While dramatic advances in targeted- and immune-based therapies have been seen in some solid tumors, they have not been reported in patients with HGSOC. Recurrent and chemoresistant HGSOC is common. Therefore, it is imperative that new HGSOC drug targets be interrogated. The Protein Tyrosine Phosphatases of Regenerating Liver (PRL or PTP4A) family is significantly upregulated in a variety of tumors, including HGSOC. A bioinformatic analysis of the ovarian cancer using the KMplot Survival Database revealed that high PTP4A3 expression was associated with poor survival in EOC (p<0.0001, hazard ratio (HR)=1.35). In HGSOC early stage disease, PTP4A3 expression levels were also correlated with survival (stage I/II- p=0.0013, HR=3.2), with low expressing patients surviving twice as long as high expressing patients (upper quartile survival in low expression cohort = 81.2 months compared to high expression cohort = 44.3 months). This survival difference appeared independent of myc amplification and was more pronounced in advanced disease (stage III/IV). qPCR profiling of established HGSOC cell lines, including Kuramochi, COV362 and OVCAR4, showed 5-20 fold increases in PTP4A3 gene expression versus nonmalignant control cells. A potent, specific, allosteric small molecule inhibitor of PTP4A3, KVX-053, markedly reduced the growth and survival of chemoresistant and chemosensitive EOC cell lines independent of their BRCA or p53 status. Moreover, treatment of the HGSOC OVCAR4 cell line with KVX-053 (1 μM) inhibited the oncogenic Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway through loss of phosphorylation of STAT3. Evaluation of a series of next-generation KVX-053-based analogs including chemodegraders yielded chemotypes with enhanced cytotoxic effects. These results demonstrate a clear path for the development of the PTP4A family of tyrosine phosphatases as a novel therapeutic target in a HGSOC. Citation Format: John Robert Cornelison, Ettore J. Rastelli, Duncan J. Hart, Anna J. Mendelson, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. PTP4A3 phosphatase is a novel drug target for epithelial ovarian 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 1459.