Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric...

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Activating mutations in PTPN11, encoding SHP2, cause developmental disorders and drive hematologic cancers.
• The allosteric inhibitor SHP099 targets wild-type SHP2 by stabilizing its autoinhibited state.
• Oncogenic mutations destabilize the autoinhibited conformation of SHP2.

Purpose of the Study:

• To investigate the structural impact of the E76K mutation on SHP2.
• To assess the effect of oncogenic mutations, including E76K, on SHP099 allosteric inhibition.
• To evaluate the efficacy of SHP099 against oncogenic SHP2 variants in vitro and in cellular models.

Main Methods:

• X-ray crystallography to determine SHP2^E76K structure.
• Biochemical assays to measure SHP099 inhibition of wild-type and mutant SHP2.
• Cell-based assays to assess SHP099 activity against oncogenic SHP2 variants.

Main Results:

• SHP2^E76K adopts an open conformation.
• SHP099 binding restores SHP2^E76K to a closed, autoinhibited conformation similar to wild-type SHP2.
• SHP099's inhibitory activity against oncogenic SHP2 inversely correlates with mutation-activating strength.

Conclusions:

• SHP099 can inhibit oncogenic SHP2 variants by inducing a closed conformation.
• More potent or oncoselective inhibitors are needed to effectively suppress signaling from strongly activating SHP2 mutations in cancer.
• Understanding mutation-specific structural impacts is crucial for developing targeted cancer therapies.