Complex Roles of PTPN11/SHP2 in Carcinogenesis and Prospect of Targeting SHP2 in Cancer Therapy

The non-receptor tyrosine phosphatase SHP2 has been at the center of cell signaling research for three decades. SHP2 is required to fully activate the RTK-RAS-ERK cascade, although the underlying mechanisms are not completely understood. PTPN11, coding for SHP2, is the first identified proto-oncogene that encodes a tyrosine phosphatase, with dominantly activating mutations detected in leukemias and solid tumors. However, SHP2 has been shown to have pro- and anti-oncogenic effects, and the most recent data reveal opposite activities of SHP2 in tumor cells and microenvironment cells. Allosteric SHP2 inhibitors show promising anti-tumor effects and overcome resistance to inhibitors of RAS-ERK signaling in animal models. Many clinical trials with orally bioactive SHP2 inhibitors, alone or combined with other regimens, are ongoing for a variety of cancers worldwide, with therapeutic outcomes yet unknown. This review discusses the multi-faceted SHP2 functions in oncogenesis, preclinical studies and clinical trials with SHP2 inhibitors in oncological treatment.