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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
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Taletrectinib promotes pyroptosis in colorectal carcinoma via SRC/AKT/mTOR axis inhibition

Ting Zhang1, Ye Zou2, Sun-Han Zhang2

  • 1School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China.

Scientific Reports
|May 23, 2025
PubMed

Insights

Taletrectinib effectively reduces colorectal cancer (CRC) cell viability by triggering gasdermin E (GSDME)-dependent pyroptosis. This targeted cell death mechanism, independent of ROS1/NTRK fusions, highlights taletrectinib

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Colorectal carcinoma (CRC) frequently develops drug resistance post-surgery, necessitating novel therapeutic strategies.
  • Taletrectinib, a ROS1/NTRK inhibitor, shows antitumor activity but its effect on CRC is not well understood.
  • Understanding resistance mechanisms and identifying new therapeutic targets in CRC is crucial.

Purpose of the Study:

  • To evaluate the in vitro and in vivo anti-cancer effects of taletrectinib on colorectal carcinoma.
  • To elucidate the underlying mechanism of taletrectinib-induced cytotoxicity in CRC cells.
  • To explore the potential of taletrectinib as a therapeutic agent for CRC.

Main Methods:

  • In vitro cytotoxicity assays using two CRC cell lines (HCT116 and LOVO).
  • In vivo efficacy evaluation in a mouse tumor model.
  • Mechanism investigation using microscopy, immunofluorescence, cell death assays (Annexin V/PI, LDH), and western blotting.
  • Transcriptome sequencing to identify genetic alterations.

Main Results:

  • Taletrectinib decreased CRC cell viability in a dose-dependent manner.
  • HCT116 and LOVO cell lines lack ROS1/NTRK gene fusions.
  • Taletrectinib induced cytotoxicity via caspase-3/gasdermin E (GSDME)-dependent pyroptosis.
  • The pyroptosis-inducing effect was reversed by the SRC agonist tolimidone.

Conclusions:

  • Taletrectinib suppresses CRC tumor growth by inducing GSDME-mediated pyroptosis.
  • The mechanism involves the SRC/AKT/mTOR signaling pathway, independent of ROS1/NTRK fusions.
  • Taletrectinib demonstrates potential as a promising therapeutic agent for colorectal carcinoma.
Keywords:
Colorectal carcinomaGSDMEPyroptosisSRCTaletrectinib

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