The role and target potential of protein tyrosine phosphatases in cancer

Abstract

Protein tyrosine phosphatases (PTPases) are attractive targets for developing novel cancer therapeutics. Activated via gain-of-function point mutations or overexpression, several PTPases have been identified as critical oncogenic molecules in human malignancies that may be targeted with small chemical inhibitors as a therapeutic strategy. Tumor suppressor PTPases have also been discovered as contributing factors in cancer development that may be targeted via intervention of downstream signaling events for therapeutic purposes. In addition, PTPases have been identified as key negative regulators of cytokines or immune cells. Targeting these negative PTPases may improve the efficacy of cytokine therapy and immunotherapy, which currently have modest response rates and limited survival benefit. Inhibitors of selective PTPases have demonstrated significant preclinical antitumor activity, leading to early-phase clinical trials. Further research and development could lead to PTPase-targeted cancer therapeutics in the near future.

Phosphatase inhibitor, sodium stibogluconate, in combination with interferon (IFN) alpha 2b: phase I trials to identify pharmacodynamic and clinical effects

“…PTPs are thus key players in human malignancies and may have potential for developing inhibitors as novel cancer therapeutics [1,5,[49][50][51]. Our data suggested tolerance of a SHP-1 inhibitor, SSG, in combination with IFN-alpha2b in cancer patients with evidence of immune regulatory activity in this study and one undertaken in parallel.…”

“…PTPs include enzymes that are oncogenic, tumor suppressive or immune regulatory [1,3,5,[48][49][50]. PTPs are thus key players in human malignancies and may have potential for developing inhibitors as novel cancer therapeutics [1,5,[49][50][51].…”

“…In particular, the PTP SHP-1 [src-homology 2 phosphatase-1, PTP1C, HCP, SHPTP-1, PTPN6] has been implicated as an attractive drug-targeting candidate by studies from our laboratory and others [2][3][4][5][6]. Expressed predominantly in cells of hematopoietic lineages [2][3][4][5][6], SHP-1 has been established as a key negative regulator of cytokine signaling and immune cell activation through detailed studies of mouse models of genetic SHP-1 deficiencies [7][8][9][10]. Accordingly, targeting SHP-1 with inhibitors might augment the efficacy of cytokine therapy and immunotherapy, which are in clinical use for cancer treatment.…”

Decreased Diacylglycerol Metabolism Enhances ERK Activation and Augments CD8+ T Cell Functional Responses

“…Both Shp-1 Ϫ/Ϫ and cbl-b Ϫ/Ϫ CD8 ϩ T cells demonstrate enhanced anti-tumor activity (3,4,41). Shp-1 Ϫ/Ϫ is a tyrosine phosphatase that acts to oppose proximal signaling components of TCR such as the tyrosine kinases Zap-70 and Lck (42).…”

Protein Tyrosine Phosphatase-Prospective Target against Cancer: A Mini Review

“…Indeed, uncontrolled phosphorylation of tyrosine site is one of the hallmarks of cancer. PTP remain captivating targets of cancer therapeutics development [16,17]. The prevalent damage of Phosphatase and tensin homolog (PTEN) occurs in various malignancies including breast and prostate cancer [18].…”