Protein tyrosine phosphatases: promising targets in pancreatic ductal adenocarcinoma.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. It is the fourth leading cause of cancer-related death and is associated with a very poor prognosis. KRAS driver mutations occur in approximately 95% of PDAC cases and cause the activation of several signaling pathways such as mitogen-activated protein kinase (MAPK) pathways. Regulation of these signaling pathways is orchestrated by feedback loops mediated by the balance between protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), leading to activation or inhibition of its downstream targets. The human PTPome comprises 125 members, and these proteins are classified into three distinct families according to their structure. Since PTP activity description, it has become clear that they have both inhibitory and stimulatory effects on cancer-associated signaling processes and that deregulation of PTP function is closely associated with tumorigenesis. Several PTPs have displayed either tumor suppressor or oncogenic characteristics during the development and progression of PDAC. In this sense, PTPs have been presented as promising candidates for the treatment of human pancreatic cancer, and many PTP inhibitors have been developed since these proteins were first associated with cancer. Nevertheless, some challenges persist regarding the development of effective and safe methods to target these molecules and deliver these drugs. In this review, we discuss the role of PTPs in tumorigenesis as tumor suppressor and oncogenic proteins. We have focused on the differential expression of these proteins in PDAC, as well as their clinical implications and possible targeting for pharmacological inhibition in cancer therapy.