Phosphatase dysregulation in cancer and therapeutic opportunities

This review was written by PhD student Maryam Jama and supervised by Dr. Barakat and Dr. Overduin (University of Alberta). This review presents a comprehensive summary of phosphatases’ role in cancer cells, and the immune tumour microenvironment (TIME).  It also evaluates their regulatory systems, signaling pathways, preclinical, and clinical studies.

Reversible protein phosphorylation is one of the most common and essential forms of cellular regulation including cell division, migration, cell death and cellular immune activities. This protein modification is a balance between kinases and phosphatase activity, which remove and add protein phosphatases, respectively. While, the dysregulation of kinases is well established in cancer biology and has led to numerous targeted therapies, the development of phosphatase-targeted drugs has lagged—not due to a lack of importance, but because of the limited understanding of their regulatory mechanisms and dynamic cellular activity.

Phosphatase dysregulation drive cancer progression by modulating RAS/MAPK, PI3K, HIPPO, and the JAK/STAT pathways. Importantly, their roles depend on the cell type, downstream substrates, and regulatory complexes. This article classifies phosphatases based on their tumour suppressive, tumour promoting or context-dependent activities. This review also examines how exosome secretion modulates phosphatase dysregulation and alters the tumour microenvironment.

SHP1 is a tumour suppressor that negatively regulates immune cell activation. SHP1 loss is associated with tumour immune evasion, while its inhibition has been shown to enhance the efficacy of immune checkpoint blockade. Other phosphatases, such as DUSP1/6, inactivate the MAPK signaling pathway, and their deletion promotes resistance to chemo- or radiotherapy and is associated with poor prognosis and metastasis.

An example of a tumour-promoting phosphatase is PRL3. Its overexpression modulates metastasis through the Hippo pathway and by enhancing chemokine receptor expression on cells. PRL3 expression on the cell surface promotes cancer cell adhesion to fibronectin and laminin and induces mesenchymal phenotypes. PRL3 inhibition suppresses cancer cell migration and exhibit anti-tumour activity in vitro and in vivo tumour models. PRL3 inhibitors—such as the monoclonal antibody PRL3-zumab and the small molecule MSI-1436C—have advanced to clinical trials.

This article also discusses phosphatases with dualistic roles in tumours, such as PTP1B, PP2A, PTPN2, and SHP2. PTP1B overexpression in tumours is associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC) patients. However, PTP1B also has tumour-suppressive roles and has been reported to reduce tumourigenicity and promote apoptosis by inhibiting receptor tyrosine kinase (RTK) signaling in cancer cells. PTP1B inhibition by a dual inhibitor (ABBV-CLS-484), suppresses tumour growth and enhances T-cell recruitment and activity, making it a promising immunotherapeutic target.

PP2A is a multimeric phosphatase capable of acting as a tumour suppressor or promoter depending on the complexes it forms. Specifically, the PP2A and the B55 and B56 subunit complex have a tumour-suppressive role. Whereas CIP2A, SET, striatin-3 (STRN3), and striatin-4 (STRN4) complex promote tumour progression by inhibiting PP2A catalytic activity. The PP2A/SET complex is overexpressed in various malignancies, including chronic lymphocytic leukemia and acute myeloid leukemia. Like other phosphatases, PP2A acts on oncogenic proteins such as ERK, AKT, YAP, and TAZ. Furthermore, PP2A suppresses immune cell activity; its inhibition promotes anti-tumour immunity. For example, LB-100, a PP2A catalytic inhibitor, enhances immune checkpoint blockade and suppresses tumour growth in in vivo tumour models. Additionally, small molecule activators of PP2A have demonstrated anti-tumor activity by inducing apoptosis in primary cancer cell lines, suggesting that both activation and inhibition of PP2A can be effective therapeutic strategies for suppressing tumour growth.

SHP2 and PTPN2 phosphatases also exhibit dualistic roles in cancer. They suppress tumour progression and modulate metabolic activity in tumour cells through STAT3, enhancing cell survival and migration. On the other hand, SHP2 and PTPN2 promote tumour growth by inducing oxidative stress, promoting inflammatory cytokine secretion, and modulating multiple RTK activities. Like PP2A, PTPN2 and SHP2 contribute to immunosuppression by suppressing responses to pro-inflammatory cytokines. Inhibitors of PTPN2 and SHP2 include the catalytic inhibitor AC484 and the allosteric inhibitor TN1055, respectively—both of which have demonstrated enhanced anti-tumour activity and immune modulation.

Phosphatases that play roles in reshaping the tumour microenvironment include SHP2, DUSP1, and PRL3, primarily through exosomal miRNA secretion. Notably, exosomal circular ubiquitin-specific protease-7 (CircUSP7) has been reported to upregulate SHP2 in non-small cell lung cancer (NSCLC). Similarly, exosomal miR-133b upregulates DUSP1 and suppresses breast cancer cell proliferation in vitro and in vivo. In immune cells, exosomal miR-138-5p downregulates SHP2, promoting anti-inflammatory M2 macrophage polarization. These exosomal miRNAs offer promising therapeutic targets for phosphatase dysregulation.

 Jama, Dr. Barakat, and Dr. Overduin summarized current therapeutics targeting these phosphatases, their mechanisms of action, and provided an updated list of drugs in clinical trials. Overall, phosphatases play parallel and distinct roles in cancer progression, immune regulation, and the broader tumour microenvironment (TME), making them excellent therapeutic targets—either alone or in combination with chemotherapy or immunotherapy. This review provides a valuable foundation for understanding how phosphatases contribute to cancer progression and highlights their growing potential as therapeutic targets.

See the article:

Phosphatase Dysregulation in Cancer: Signaling Pathways and Therapeutic Opportunities

https://doi.org/10.1002/mog2.70028