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mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity

Zhe-Zhu Jin1, Wei Wang1, Di-Long Fang1

  • 1Department of Colorectal Surgery, Hangzhou Red Cross Hospital, Hangzhou, China.

Biochemical and Biophysical Research Communications
|August 28, 2016
PubMed

Insights

ONC201 shows anti-colorectal cancer (CRC) activity by inducing cell death. Inhibiting mTOR kinase enhances ONC201

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Colorectal cancer (CRC) remains a significant health challenge.
  • Targeting molecular pathways offers potential therapeutic strategies.
  • ONC201 is a novel small molecule with potential anti-cancer activity.

Purpose of the Study:

  • To evaluate the anti-CRC activity of ONC201.
  • To investigate the role of mTOR in ONC201's mechanism of action.
  • To explore combination therapy with ONC201 and mTOR inhibitors.

Main Methods:

  • Cytotoxicity assays on CRC cell lines and primary cells.
  • Western blotting to assess protein expression and activation (TRAIL, DR-5, caspase-8, Akt, mTOR, S6K1).
  • Genetic manipulation including kinase-dead mutations and shRNA knockdown of mTOR.

Main Results:

  • ONC201 demonstrated moderate cytotoxicity against CRC cells.
  • mTOR kinase inhibition (AZD-8055) significantly sensitized CRC cells to ONC201.
  • Combination therapy enhanced TRAIL/DR-5 expression, caspase-8 activation, and apoptosis.
  • mTOR kinase-dead mutations or knockdown sensitized cells to ONC201, while active S6K1 attenuated apoptosis.
  • ONC201 primarily blocked Akt, with only slight mTOR inhibition, which was enhanced by AZD-8055.

Conclusions:

  • mTOR kinase activity is a key resistance factor for ONC201 in colorectal cancer.
  • Combining ONC201 with mTOR inhibitors may overcome resistance and enhance anti-CRC efficacy.
  • Targeting the mTOR pathway alongside TRAIL induction presents a promising therapeutic approach for CRC.
Keywords:
AZD-8055Colorectal cancerONC201TRAILmTOR

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