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SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase

Yuko Nagamura1, Makoto Miyazaki1, Yoshiko Nagano1

  • 1Department of Cancer Cell Research, Sasaki Institute, Sasaki Foundation, Tokyo 101-0062, Japan.

Cancers
|September 10, 2021
PubMed

Insights

Targeting SHP2 phosphatase may treat aggressive diffuse-type gastric carcinoma (DGC). SHP2 is crucial for DGC progression driven by Met or FGFR2 gene amplification, even with resistance to inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Diffuse-type gastric carcinoma (DGC) is aggressive, characterized by infiltrative growth, fibrosis, and peritoneal spread.
  • Gene amplification of Met and fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinases (RTKs) is implicated in DGC.
  • Signaling pathways downstream of these RTKs driving DGC progression require further elucidation.

Purpose of the Study:

  • To characterize the role of SHP2 tyrosine phosphatase in DGC progression.
  • To evaluate SHP2 as a therapeutic target in DGC.
  • To investigate SHP2's function in RTK-addicted DGC cells.

Main Methods:

  • Phospho-proteomic analysis to identify SHP2 in DGC cells with Met amplification.
  • Assessment of SHP2 tyrosine phosphorylation in various gastric carcinoma cell lines.
  • Inhibition of Met/FGFR signaling and SHP2 (pharmacological/knockdown) in DGC models.
  • In vitro assays for cell growth, migration, and invasion.
  • In vivo mouse xenograft model for peritoneal dissemination.

Main Results:

  • SHP2 tyrosine phosphorylation was elevated in DGC cells with Met or FGFR2 gene amplification.
  • Met or FGFR inhibition reduced SHP2 tyrosine phosphorylation.
  • SHP2 inhibition selectively suppressed growth of DGC cells dependent on Met/FGFR2, including those resistant to Met inhibitors.
  • SHP2 inhibition blocked migration, invasion, and peritoneal dissemination of Met-addicted DGC cells.

Conclusions:

  • SHP2 is a critical regulator of malignant progression in RTK-addicted DGC.
  • Targeting SHP2 represents a potential therapeutic strategy for DGC.
  • SHP2 plays a key role in the aggressive phenotypes of DGC driven by Met/FGFR2 signaling.
Keywords:
MetSHP2diffuse-type gastric carcinomaperitoneal disseminationreceptor tyrosine kinase

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