SHP2 (PTPN11)

aka SHP-2, PTP2C, SH-PTP2, protein tyrosine phosphatase non-receptor type 11

SHP2 is an enzyme that sits between growth-factor receptors and RAS and keeps the RAS signal flowing. Blocking it removes the route by which KRAS-driven tumours bounce back from a KRAS inhibitor, which is why SHP2 inhibitors are being paired with KRAS G12C drugs.

PTPN11 (chromosome 12q24.13) encodes SHP2, a cytoplasmic tyrosine phosphatase that acts downstream of receptor and cytoplasmic tyrosine kinases, positively regulates MAPK signalling and dephosphorylates GAB1, EGFR, ROCK2, CDC73 and other substrates; it is also the effector recruited by phosphorylated PD-1 to dephosphorylate T-cell receptor signalling components (UniProt Q06124). In OnCo, SHP2 is the target of the second-generation allosteric inhibitor sitneprotafib (JAB-3312), combined with the KRAS G12C inhibitor glecirasib in NSCLC, colorectal and pancreatic cancer, and the combination partner named in the garsorasib and glecirasib records.

SHP2 (PTPN11): what it is and how drugs act on it · animated schematic, not to scale

Target · the protein and the cell it sits on
Drug · antibody, small molecule, cell or radioligand
Effect · signal, damage or kill

In plain words · SHP2 is an enzyme that sits between growth-factor receptors and RAS and keeps the RAS signal flowing. Blocking it removes the route by which KRAS-driven tumours bounce back from a KRAS inhibitor, which is why SHP2 inhibitors are being paired with KRAS G12C drugs.

1 · What it is
SHP2 is an enzyme that sits between growth-factor receptors and RAS and keeps the RAS signal flowing. Blocking it removes the route by which KRAS-driven tumours bounce back from a KRAS inhibitor, which is why SHP2 inhibitors are being paired with KRAS G12C drugs.
2 · What goes wrong in cancer
Because SHP2 relays receptor signals into RAS, inhibiting it blocks the upstream reactivation that limits KRAS inhibitors, and its role in PD-1 signalling gives a second rationale in immunotherapy combinations.
3 · How drugs use it
1 product aims at SHP2 (PTPN11): small molecules. Inhibitors are shaped to fit the enzyme's active site so the reaction the cancer relies on stops.

Full dossier: hotspots, trials, resistance, assays, models, open questions →

External identifiers

PTPN11HGNCEnsemblUniProtAlphaFold DBOpen TargetsCIViCOncoKBCOSMICcBioPortalDepMapHuman Protein AtlasNCBI GeneOMIM

Biology

Because SHP2 relays receptor signals into RAS, inhibiting it blocks the upstream reactivation that limits KRAS inhibitors, and its role in PD-1 signalling gives a second rationale in immunotherapy combinations. Sitneprotafib is described as allosteric, with more potent anti-tumour activity than earlier SHP2 inhibitors.

Where it is found

KRAS G12C-mutant NSCLC and colorectal cancer (combination trials with KRAS inhibitors)
Pancreatic cancer (sitneprotafib trials)

Class

enzyme · PTPN11

Identifiers

HGNC HGNC:9644Ensembl ENSG00000179295UniProt Q06124NCBI Gene 5781

Products

1top

Phase 3small molecule

Sitneprotafib

Sitneprotafib is an experimental small-molecule drug from Allist Pharmaceuticals in phase 3 trials for non-small-cell lung cancer, colorectal cancer and pancreatic ductal adenocarcinoma, with its target not yet stated publicly.