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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.
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.
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.
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.
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.
Broadly expressed or essential: HPA lists PTPN11 among essential proteins and finds the RNA at low tissue specificity; the 1 medicine aimed at it (Sitneprotafib) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA PTPN11: RNA low tissue specificity; high antibody staining in 21 normal tissues; highest cancer staining head and neck cancer (4 of 4 high). Distribution: 3 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Lung cancer (all types), Colorectal cancer, Pancreatic ductal adenocarcinoma); Open Targets associates it with 2 specific cancer types at or above 0.5 (juvenile myelomonocytic leukemia, acute myeloid leukemia). (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas PTPN11 tissue; Open Targets ENSG00000179295 associations
First described 1992. Earliest sequence paper UniProt cites for the protein: Adachi et al, FEBS Lett, 1992, "Molecular cloning of a novel protein-tyrosine phosphatase SH-PTP3 with sequence similarity to the src-homology region 2". Source.
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.
RNA: low tissue specificity, detected in all normal tissues.
Medium: Breast, Bronchus, Cervix, Duodenum, Esophagus, Kidney, Nasopharynx, Oral mucosa.
Medium only: carcinoid, renal cancer, thyroid cancer.
HPA PTPN11 tissue · HPA PTPN11 pathology · HPA protein class: Essential proteins
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
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.
Query for this target: (TITLE:"SHP2" OR ABSTRACT:"SHP2" OR TITLE:"PTPN11" OR ABSTRACT:"PTPN11" OR TITLE:"SHP-2" OR ABSTRACT:"SHP-2" OR TITLE:"PTP2C" OR ABSTRACT:"PTP2C" OR TITLE:"SH-PTP2" OR ABSTRACT:"SH-PTP2" OR TITLE:"protein tyrosine phosphatase non-receptor type 11" OR ABSTRACT:"protein tyrosine phosphatase non-receptor type 11") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about SHP2 (PTPN11), not a curated reading list.
Shares Resistance routes: how a blocked pathway comes back, KRAS, Small-molecule kinase inhibitors, Pancreatic ductal adenocarcinoma and the tag wave5-target.
Shares RAS / RAF / MEK / ERK (MAPK), KRAS, Small-molecule kinase inhibitors, Non-small-cell lung cancer and the tag wave5-target.
Shares KRAS & RAS inhibitors, RAS / RAF / MEK / ERK (MAPK), KRAS, Colorectal cancer and the tag wave5-target.
Shares PD-1 / PD-L1 immune checkpoint & T-cell activation, Non-small-cell lung cancer and the tag wave5-target.
Shares PD-1 / PD-L1 immune checkpoint & T-cell activation, Non-small-cell lung cancer and the tag wave5-target.
Shares PD-1 / PD-L1 immune checkpoint & T-cell activation and the tag wave5-target.
Shares Small-molecule kinase inhibitors and the tag wave5-target.
Shares Small-molecule kinase inhibitors and the tag wave5-target.