Related Experiment Video

Updated: Sep 11, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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A Hotspot Phosphorylation Site on SHP2 Drives Oncoprotein Activation and Drug Resistance

Neil Vasan1,2,3, Prashath Karunaraj1, Remkes Scheele4

  • 1Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.

Research Square
|August 13, 2025
PubMed

Insights

Phosphorylation of SHP2 at tyrosine 62 (pY62) by SRC family kinases causes resistance to SHP2 inhibitors by activating MAPK signaling. This pY62 site represents a novel cancer drug target distinct from wildtype SHP2.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • SHP2 phosphatase is crucial for receptor tyrosine kinase (RTK)-driven RAS/MAPK signaling.
  • SHP2 inhibitors show limited clinical efficacy, with resistance mechanisms unclear.

Purpose of the Study:

  • To identify mechanisms of primary resistance to SHP2 inhibitors.
  • To investigate the role of SHP2 phosphorylation in cancer signaling and drug resistance.

Main Methods:

  • Proteomic analysis to identify SHP2 phosphorylation hotspots.
  • Biochemical assays to determine kinase activity and protein interactions.
  • Biophysical analyses to characterize SHP2 conformation and activation.

Main Results:

  • Phosphorylation of SHP2 at tyrosine 62 (pY62) is a hotspot in RTK-driven tumors.
  • SRC family kinases directly phosphorylate SHP2 at Y62, independent of direct RTK phosphorylation.
  • SHP2 Y62D mutation mimics constitutive activation, leading to MAPK pathway activation and resistance to allosteric SHP2 inhibitors.

Conclusions:

  • SHP2 pY62 phosphorylation is a mechanism of primary resistance to SHP2 inhibitors, phenocopying mutational activation.
  • Targeting SHP2 pY62 offers a distinct therapeutic strategy separate from wildtype SHP2 inhibition.

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