A Hotspot Phosphorylation Site on SHP2 Drives Oncoprotein Activation and Drug Resistance

This study identifies phosphorylation of SHP2 at tyrosine 62 (pY62) as a conserved mechanism of resistance to allosteric SHP2 inhibitors. By stabilizing an open, active SHP2 conformation, pY62 phenocopies oncogenic PTPN11 mutations and sustains MAPK signaling across cancer
types. These findings redefine SHP2 inhibitor resistance as a phosphorylation-driven, target- intrinsic process, nominate pY62 as a potential biomarker for therapeutic response, and propose phosphorylated SHP2 as a distinct drug target.