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Updated: Apr 27, 2026

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

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Oncogenic KIT-induced aggressive systemic mastocytosis requires SHP2/PTPN11 phosphatase for disease progression in

Namit Sharma1, Stephanie Everingham1, Li-Fan Zeng2

  • 1Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6; Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada K7L 3N6.

Oncotarget
|July 16, 2014
PubMed

Insights

SHP2 phosphatase is crucial for oncogenic KIT signaling in aggressive systemic mastocytosis (SM). Inhibiting SHP2 reduces cancer cell growth and survival, offering a potential new therapeutic strategy for SM patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Hematology

Background:

  • Acquired KIT mutations drive systemic mastocytosis (SM).
  • The role of SHP2 phosphatase in oncogenic KIT signaling in SM remains unclear.
  • Understanding SHP2's function is vital for developing targeted therapies.

Purpose of the Study:

  • To investigate the role of SHP2 phosphatase in oncogenic KIT signaling in aggressive SM.
  • To evaluate SHP2 as a potential therapeutic target in SM.

Main Methods:

  • Utilized an aggressive SM mouse model with P815 cells.
  • Performed stable knock-down (KD) of SHP2 in P815 cells.
  • Administered SHP2 inhibitor II-B08 and Dasatinib to human and mouse cell lines.
  • Assessed disease progression, signaling pathways, cell viability, and colony formation.

Main Results:

  • SHP2 KD in P815 cells impaired growth, colony formation, and induced apoptosis.
  • SHP2 KD reduced signaling to ERK/Bim, Btk, Lyn, and Stat5 pathways.
  • Mice injected with SHP2 KD cells exhibited significantly less aggressive SM.
  • SHP2 inhibition reduced cell viability and colony formation in human and mouse mastocytosis cells.
  • Combined SHP2 inhibition and Dasatinib showed enhanced efficacy.

Conclusions:

  • SHP2 is a key effector of oncogenic KIT signaling in aggressive SM.
  • Targeting SHP2, alone or in combination with other inhibitors, demonstrates therapeutic potential for SM.

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