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Updated: Oct 13, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Therapeutic Suppression of FAK-AKT Signaling Overcomes Resistance to SHP2 Inhibition in Colorectal Carcinoma

Ye Li1,2, Yuncang Yuan3, Fan Zhang2

  • 1Department of Digestive Endoscopy, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Frontiers in Pharmacology
|November 18, 2021
PubMed

Insights

SHP2 inhibitors show promise for cancer treatment, but resistance is common in colorectal cancer. Reactivation of the AKT pathway drives this resistance, suggesting combined AKT or FAK inhibition can improve treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • SHP2 (Src homology 2 domain-containing phosphatase 2) is a key regulator of receptor tyrosine kinase (RTK) signaling to ERK and AKT pathways.
  • SHP2 inhibitors represent a promising cancer therapy, but their efficacy in colorectal carcinoma (CRC) and resistance mechanisms are not fully understood.
  • While ERK signaling is well-studied post-SHP2 inhibition, AKT pathway alterations in CRC remain largely unexplored.

Purpose of the Study:

  • To investigate the role and significance of phosphorylated SHP2 (p-SHP2) in colorectal carcinoma (CRC).
  • To explore the impact of SHP2 inhibition on AKT signaling in CRC cells and identify resistance mechanisms.
  • To evaluate combination strategies involving SHP2 inhibitors with AKT or focal adhesion kinase (FAK) inhibitors to overcome resistance and enhance anti-tumor efficacy.

Main Methods:

  • Immunohistochemistry and bioinformatics analyses were performed to assess p-SHP2 in CRC.
  • CRC cell lines were treated with the SHP2 inhibitor SHP099 to evaluate effects on viability and signaling pathways.
  • Combination therapies with AKT inhibitors and FAK inhibitors were tested in vitro and in vivo.

Main Results:

  • Frequent resistance to SHP2 inhibition was observed in CRC cells, irrespective of RAS mutation status.
  • SHP2 inhibition led to rapid adaptive reactivation of the AKT pathway, potentially mediated by RTK or p-FAK reactivation.
  • High baseline p-FAK levels correlated with resistance to SHP2 inhibitors.
  • Co-inhibition of FAK effectively blocked AKT pathway feedback reactivation following SHP2 inhibition.
  • Combined SHP2 and AKT or FAK inhibition resulted in sustained AKT suppression and improved anti-tumor effects.

Conclusions:

  • AKT pathway reactivation is a critical mechanism of adaptive resistance to SHP2 inhibitors in CRC.
  • Targeting AKT or FAK signaling in combination with SHP2 inhibitors offers a viable strategy to enhance therapeutic efficacy.
  • These findings highlight the potential of combined inhibition strategies for improving CRC treatment outcomes.
Keywords:
AKT reboundFAKSHP2colorectal carcinomadrug resistance

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