The PTPN11gene encodes SHP-2, a widely expressed cytoplasmic protein tyrosine phosphatase. SHP-2 is essential for activation of the RAS/MAPK signaling cascade. Most mutations are gain-of-function and result in prolonged ligand-dependent activation of the RAS/MAPK cascade. Germ-line PTPN11 mutations cause Noonan syndrome, a developmental disorder characterized by an increased risk of malignancies. Activating somatic mutations in PTPN11 have been documented in certain hematologic malignancies but they are infrequent in solid tumors. About 3% of all lung cancers harbor somatic mutations in PTPN11 gene but their prognostic and therapeutic significance remains to be fully elucidated. The utility of SHP2 inhibitors continues to be explored in some preclinical studies.
- Martinelli S, et al. Activating PTPN11 mutations play a minor role in pediatric and adult solid tumors. Cancer Genet Cytogenet 2006;166(2):124-9
- Rizvi NA, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348(6230):124-8
- Qu CK The SHP-2 tyrosine phosphatase: signaling mechanisms and biological functions. Cell Res 2000;10(4):279-88
- Tartaglia M, et al. Germ-line and somatic PTPN11 mutations in human disease. Eur J Med Genet 2005;48(2):81-96
- Grosskopf S, et al. Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo. ChemMedChem 2015;10(5):815-26
- Yu B, et al. Targeting protein tyrosine phosphatase SHP2 for the treatment of PTPN11-associated malignancies. Mol Cancer Ther 2013;12(9):1738-48
- Bentires-Alj M, et al. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res 2004;64(24):8816-20