Abstract 5500: A PTP4A3 inhibitor reduces ovarian cancer dissemination and alters STAT3 and ERK activation

Abstract

Abstract The objective of this study was twofold: (1) to examine the pharmacological effects of a potent, allosteric, small molecule inhibitor (KVX-053 or 7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione) of the oncogenic protein tyrosine phosphatase PTP4A3, which is overexpressed in human ovarian cancer and is associated with poor patient prognosis, and (2) to define alterations in ovarian cancer cells with acquired resistance to this PTP4A3 phosphatase inhibitor. PTP4A3 promotes cell migration, survival, metabolism, angiogenesis, and tumor formation, which are mediated at least partly by PTP4A3’s ability to function as a positive signal transducer capable of activating STAT3 and ERK1/2. We found KVX-053 inhibited the migration and, at higher concentrations, the viability of chemosensitive and chemoresistant human ovarian cancer cell lines in vitro. Using an established ovarian cancer metastasis prevention model in which taxane-resistant SKOV3TRip2 cells were injected i.p. followed by four treatments with 20 mg/kg KVX-053, we observed a median survival of 68 days compared to the median survival of 58 days in the vehicle treated mice. We also observed a statistically significant reduction in the number of tumor implantation sites with KVX-053 treatment. Since drug resistance frequently occurs with targeted cancer therapies, we next generated A2780 and OVCAR4 ovarian cancer cells that were 32- and 4-fold resistant to KVX-053, respectively. This was accomplished by using stepwise increased compound exposure over a 3-4 month period to probe acquired cellular resistance changes caused by KVX-053. The resulting KVX-053-resistant cells had similar in vitro growth rates with the wildtype cells and retained resistance to KVX-053 for at least one month when grown in the absence of the small molecule inhibitor. They were not cross-resistant to paclitaxel, cisplatin or teniposide but were cross-resistant to chemical analogs of KVX-053. The KVX-053-resistant A2780 cells exhibited a 95% decrease in the activated form of STAT3, Y705 phospho-STAT3, and a 57% decrease in the phosphorylation of a second activation site S727 without any marked differences in the total STAT3 levels. In contrast, phospho-ERK1/2 and total ERK1/2 were elevated in the ovarian cancer cells with stable resistance to KVX-053. These results further confirm the in vivo activity of KVX-053 against ovarian cancer and suggest that chronic KVX-053 exposure disrupts the PTP4A3/STAT3 and PTP4A3/ERK cellular signaling pathways. Citation Format: John S. Lazo, Kelly N. Isbell, Danielle C. Llaneza, Ettore J. Rastelli, Charles N. Landen, Peter Wipf, Elizabeth R. Sharlow. A PTP4A3 inhibitor reduces ovarian cancer dissemination and alters STAT3 and ERK activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5500.