PTPN11 and cancer: Due to its critical role in signal transduction between receptor tyrosine kinases (RTKs) and RAS, SHP2 modulates RAS-dependent ERK, mTOR, and JAK/STAT signaling pathways.20,21 SHP2-dependent RAS activation can drive adaptive resistance to MEK inhibitors in some cancers, and SHP2 inhibition with small molecule inhibitors (SHP2i) can prevent or overcome adaptive resistance to MEK inhibitors,22–25 making them promising clinical candidates when combined with other targeted therapies such as FGFR, tyrosine kinase, and BRAF inhibitors.25,26