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Tumor microenvironment confers mTOR inhibitor resistance in invasive intestinal adenocarcinoma

T Fujishita1,2, Y Kojima1, R Kajino-Sakamoto1

  • 1Division of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan.

Oncogene
|August 1, 2017
PubMed

Insights

mTOR inhibitors like everolimus can reduce intestinal tumor growth but face resistance. Combining mTOR inhibitors with EGFR or MEK inhibitors may overcome this resistance by targeting feedback signaling in the tumor microenvironment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is frequently activated in cancers.
  • Clinical mTORC1 inhibitors like everolimus and temsirolimus are used, but drug resistance is a major challenge.
  • Dual mTORC1/2 inhibitors are under development for various malignancies.

Purpose of the Study:

  • To investigate the efficacy of mTOR inhibitors in a mouse model of invasive intestinal adenocarcinoma.
  • To explore the mechanisms of resistance to mTOR inhibitors in this model.
  • To evaluate combination therapies involving mTOR inhibitors and signaling pathway inhibitors.

Main Methods:

  • Utilized the cis-Apc/Smad4 mouse model for locally invasive intestinal adenocarcinoma.
  • Administered everolimus (mTORC1 inhibitor) and AZD8055 (dual mTORC1/2 inhibitor).
  • Performed biochemical and immunohistochemical analyses to assess signaling pathways (EGFR, MEK/ERK).
  • Evaluated combination therapies with EGFR inhibitor (erlotinib) or MEK inhibitor (trametinib).

Main Results:

  • Everolimus and AZD8055 significantly reduced intestinal tumor growth.
  • mTOR inhibitors delayed tumor invasion at early stages but were less effective later.
  • Treatment induced increased epidermal growth factor receptor (EGFR) and MEK/ERK signaling.
  • Combination therapy with AZD8055 and erlotinib or trametinib suppressed tumor invasion.

Conclusions:

  • mTOR inhibitor resistance in invasive intestinal tumors involves feedback signaling from cancer and stromal cells.
  • The tumor microenvironment plays a critical role in drug resistance.
  • Simultaneous inhibition of mTOR and EGFR or MEK pathways may offer a more effective treatment strategy for colon cancer.

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