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Updated: Oct 4, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

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Allosteric inhibition reveals SHP2-mediated tumor immunosuppression in colon cancer by single-cell transcriptomics

Jian Gao1, Zhigui Wu1, Mingxia Zhao1,2

  • 1State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Life Sciences, Nanjing University, Nanjing 210023, China.

Acta Pharmaceutica Sinica. B
|February 7, 2022
PubMed

Insights

SHP2 inhibition with SHP099 halts colorectal cancer (CRC) progression by activating anti-tumor immunity in myeloid cells. This finding highlights SHP2 as a potential therapeutic target for colon cancer immunotherapy, particularly in microsatellite-stable tumors.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Colorectal cancer (CRC) presents microsatellite instability (MSI) or stable (MSS) phenotypes.
  • SHP2 is a potential cancer therapy target, but its role in innate immunosuppression is unclear.

Purpose of the Study:

  • To investigate the role of SHP2 in the tumor microenvironment (TME) of colorectal cancer.
  • To explore the therapeutic potential of SHP2 inhibition in CRC.

Main Methods:

  • Single-cell RNA sequencing of murine MC38 xenografts.
  • Treatment with SHP099, a SHP2 allosteric inhibitor.

Main Results:

  • SHP099 treatment arrested malignant tumor cell evolution.
  • SHP099 activated STING-TBK1-IRF3-mediated type I interferon signaling in myeloid cells.
  • MSS CRC patients showed increased macrophage infiltration and SHP2 phosphorylation in CD68+ macrophages.

Conclusions:

  • SHP2 mediates innate immunosuppression in colorectal cancer.
  • Targeting SHP2 with inhibitors like SHP099 shows promise for colon cancer immunotherapy, especially in MSS tumors.
Keywords:
APC, antigen-presenting cellBTLA, B- and T-lymphocyte attenuatorCNVs, copy number variationsCRC, colorectal cancerColorectal cancerDSBs, double-strand breaksGSEA, gene set enrichment analysisKRAS, Kirsten rat sarcoma viral oncogene homologMAPK, mitogen-activated kinaseMSI, microsatellite instabilityMSS, microsatellite stableMacrophagePCA, principal component analysisPD-1, programmed cell death 1PTPN11SHP099STINGSTING, stimulator of interferon genesTME, tumor microenvironmentTumor microenvironmentType I interferonscRNA-seqscRNA-seq, single-cell RNA-sequencingt-SNE, t-distributed stochastic neighbor embedding

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