Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer

Lazo, John S.; Sharlow, Elizabeth R.; Cornelison, Robert; Hart, Duncan J.; Llaneza, Danielle C.; Mendelson, Anna J.; Rastelli, Ettore J.; Tasker, Nikhil R.; Landen, Charles N.; Wipf, Peter

doi:10.3390/biom11070969

Cited by 9 publications

(19 citation statements)

References 39 publications

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“…Because of the central role that has been proposed for IL-6 in the STAT3/PTP4A3 feedforward loop (Chong et al, 2019), we predicted that alterations in STAT3 activation would disrupt IL-6 stimulated phenotypic properties of cells. As we have previously demonstrated (Lazo et al, 2021), IL-6 stimulates OvCa cell migration, which is inhibited by JMS-053 (Fig. 8E).…”

Section: Acute Exposure To Jms-053 Alters the Phosphorylation Status ...supporting

confidence: 82%

“…We focused the remainder of our attention on potential differences in the intracellular signaling pathways in the OVCAR4 cell population for several reasons. First, because, unlike A2780 cells, OVCAR4 cells are a well-accepted model of high grade serous OvCa, which is the most lethal form of the disease and is generally intrinsically drug resistant (Lengyel, 2010;Cowley et al, 2014;Lazo et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The Protein Tyrosine Phosphatases of Regenerating Liver oncoprotein (PTP4A3 or PRL-3) is one of the most oncogenic, known, protein tyrosine phosphatases (PTPs), promoting tumor formation, cell survival, migration, metabolism, and angiogenesis (Yu and Zhang, 2017;Lazo et al, 2021). It is significantly upregulated in more than 75% of all human tumors (Thura et al, 2019), most notably ovarian cancer (OvCa) (Polato et al, 2005;McQueeney et al, 2018b;Lazo et al, 2021). Drug resistance and tumor recurrence remain serious problems for patients with OvCa, which represents multiple histologically and genetically distinct subtypes that, unlike some other tumor types, have generally not responded well to molecularly targeted drugs.…”

Section: Introductionmentioning

confidence: 99%

“…We previously described the design and synthesis of the potent, allosteric, small molecule PTP4A3 inhibitor, 7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione (also known as JMS-053 or KVX-053) (Salamoun et al, 2016;Tasker et al, 2019) and demonstrated in vitro cytotoxicity against multiple chemosensitive and chemoresistant human OvCa cell lines (McQueeney et al, 2018b;Lazo et al, 2021). Importantly, no significant cell death was observed with normal IMR-90 fibroblast and ovarian surface epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

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Disruption of Ovarian Cancer STAT3 and p38 Signaling with a Small-Molecule Inhibitor of PTP4A3 Phosphatase

Lazo

Isbell

Vasa

et al. 2023

J Pharmacol Exp Ther

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Protein tyrosine phosphatase type IVA member 3 (PTP4A3 or PRL-3) is a nonreceptor, oncogenic, dual-specificity phosphatase that is highly expressed in many human tumors, including ovarian cancer, and is associated with a poor patient prognosis.Recent studies suggest PTP4A3 directly dephosphorylates SHP-2 phosphatase as part of a STAT3-PTP4A3 feedforward loop and directly dephosphorylates p38 kinase. The goal of the current studies was to examine the effect of a PTP4A phosphatase inhibitor, 7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione or JMS-053, on ovarian cancer STAT3, SHP-2, and p38 kinase phosphorylation. JMS-053 caused a concentration-and time-dependent decrease in the activated form of STAT3, Y 705 phospho-STAT3, in ovarian cancer cells treated in vitro. In contrast, the phosphorylation status of two previously described direct PTP4A3 substrates, SHP-2 phosphatase and p38 kinase, were rapidly increased with JMS-053 treatment. We generated A2780 and OVCAR4 ovarian cancer cells resistant to JMS-053 and the resulting cells were not crossresistant to paclitaxel, cisplatin or teniposide. JMS-053-resistant A2780 and OVCAR4 cells exhibited a 95% and 50% decrease in basal Y 705 phospho-STAT3, respectively. JMS-053-resistant OVCAR4 cells had an attenuated phosphorylation and migratory response to acute exposure to JMS-053. These results support a regulatory role for PTP4A phosphatase in ovarian cancer cell STAT3 and p38 signaling circuits.

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Section: Acute Exposure To Jms-053 Alters the Phosphorylation Status ...supporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Disruption of Ovarian Cancer STAT3 and p38 Signaling with a Small-Molecule Inhibitor of PTP4A3 Phosphatase

Lazo

Isbell

Vasa

et al. 2023

J Pharmacol Exp Ther

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Applications of single-cell RNA sequencing in drug discovery and development

Sande

Lee

Mutasa-Gottgens

et al. 2023

Nat Rev Drug Discov

132

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Single-cell technologies, particularly single-cell RNA sequencing (scRNA-seq) methods, together with associated computational tools and the growing availability of public data resources, are transforming drug discovery and development. New opportunities are emerging in target identification owing to improved disease understanding through cell subtyping, and highly multiplexed functional genomics screens incorporating scRNA-seq are enhancing target credentialling and prioritization. ScRNA-seq is also aiding the selection of relevant preclinical disease models and providing new insights into drug mechanisms of action. In clinical development, scRNA-seq can inform decision-making via improved biomarker identification for patient stratification and more precise monitoring of drug response and disease progression. Here, we illustrate how scRNA-seq methods are being applied in key steps in drug discovery and development, and discuss ongoing challenges for their implementation in the pharmaceutical industry.

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Development and characterization of nanobodies specifically targeting the oncogenic Phosphatase of Regenerating Liver-3 (PRL-3)

Smith

Min

Williamson

et al. 2020

Preprint

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Protein Tyrosine Phosphatase 4A3 (PTP4A3 or PRL-3) is an oncogenic dual specificity phosphatase that drives tumor metastasis, promotes cancer cell survival, has been linked to poor patient prognosis in a variety of tumor types. The mechanisms by which PRL-3 promotes tumor progression are not well understood, which is in part due to lack of tools to study this protein. The development of small molecule inhibitors that are specific to PRL-3 has proven difficult, as the PRL family is >80% homologous. As research tools, antibodies directed against PRL-3 have been more successful, although they are limited to certain assay types. To address this, we have designed, purified, and tested alpaca-derived PRL-3 single domain antibodies, or nanobodies. We have identified 7 unique nanobodies that bind to PRL-3 in ELISA with no activity towards PRL-1 and PRL-2. Anti-PRL-3 nanobodies immunoprecipitated PRL-3 from cell lysates and were used to define PLR-3 localization in human colon cancer cells in immunofluorescence cell staining experiments. These anti-PRL-3 nanobodies represent an important expansion of the tool set used for the study of PRL-3, and can be used to better define the role of PRL-3 in cancer progression while serving as a useful first step in the development of biologics to target PRL-3 in the clinic.

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Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer

Cited by 9 publications

References 39 publications

Disruption of Ovarian Cancer STAT3 and p38 Signaling with a Small-Molecule Inhibitor of PTP4A3 Phosphatase

Disruption of Ovarian Cancer STAT3 and p38 Signaling with a Small-Molecule Inhibitor of PTP4A3 Phosphatase

Applications of single-cell RNA sequencing in drug discovery and development

Development and characterization of nanobodies specifically targeting the oncogenic Phosphatase of Regenerating Liver-3 (PRL-3)

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