Eight novel pathogenic variants were detected and clinical features because of specific genetic variants were reported, including hearing loss, cancer risk due to a PTPN11 pathogenic variant, and ubiquitous abnormal intracranial structure due to SHOC2 pathogenic variants.
Our findings identify an important role of SHP2 in promoting proliferation and survival of GAB2<sup>High</sup> ovarian cancer cells, and combinatorial SHP2 and PI3K inhibition may be a promising therapeutic approach for such cancer.
Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is ubiquitously expressed in cytoplasmic localization, which in turn confers tumor malignancy and poor prognosis in various human cancers.
Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway.
Finding selective inhibitors for Shp2 is useful because although its inhibition is advantageous for the treatment of some types of cancer, inhibition of Shp1 may have the opposite effect, since it acts as a suppressor of tumors.
Many studies have reported that upregulation of SHP2 expression is closely related to human cancer, such as breast cancer, liver cancer and gastric cancer.
Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation.
With respect to the immune system, the role of SHP-2 in the signaling of cytokines relevant for myelopoiesis and myeloid malignancies has been intensively studied.
These results indicate that inhibition of SHP2 and its downstream pathways by the two compounds might be a promising strategy for cancer therapy in some but not all cancer types.
The Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp2) is generally considered to be an oncogene owing to its ability in enhancing the malignancy of multiple types of tumor cells; however, its role in modulating tumor immunity remains largely elusive.
Fedele and colleagues demonstrate that SHP2 inhibitors prevent adaptive MEK inhibitor resistance; therefore, combining MEK and SHP2 inhibitors represents an exciting new therapeutic approach for the treatment of RAS-driven cancers.<i>Cancer Discov; 8(10); 1210-2.
Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS-RAF-MEK-ERK pathway<sup>11,12</sup>, was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines<sup>13</sup>.
This work illustrates a rare example of dual allosteric targeted protein inhibition, demonstrates screening methodology and tactics to identify allosteric inhibitors, and enables further interrogation of SHP2 in cancer and related pathologies.
We find that SHP2/MEK inhibitor combinations prevent adaptive resistance in multiple cancer models expressing mutant and wild-type KRAS.<i>Cancer Discov; 8(10); 1237-49.
Due to the involvement of SHP2 (SH2 domain-containing protein-tyrosine phosphatase) in human disease, including Noonan syndrome and cancer, several inhibitors targeting SHP2 have been developed.
SHP099 inhibitory activity against oncogenic SHP2 variants in vitro and in cells scales inversely with the activating strength of the mutation, indicating that either oncoselective or vastly more potent inhibitors will be necessary to suppress oncogenic signaling by the most strongly activating SHP2 mutations in cancer.
Gain-of-function (GOF) or loss-of-function (LOF) SHP2 in various cells, especially for stem cells, disrupt organism self-balance and lead to a plethora of diseases, such as cancer, maldevelopment, and excessive hyperblastosis.
The protein tyrosine phosphatase PTPN11 is implicated in the pathogenesis of juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), and other malignancies.
SHP2 (Src homology 2 domain-containing protein tyrosine phosphatase 2; PTPN11) is a ubiquitous multidomain, nonreceptor protein tyrosine phosphatase (PTP) that plays an important role in diseases such as cancer, diabetes, and Noonan syndrome (NS).