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Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition

F Mateo1, E J Arenas2, H Aguilar1

  • 1Breast Cancer and Systems Biology Laboratory, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain.

Oncogene
|December 20, 2016
PubMed

Insights

Mechanistic target of rapamycin (mTOR) inhibitors fail in breast cancer due to EVI1 and SOX9 driving transcriptional reprogramming. These factors promote metastasis and resistance to mTOR inhibition, revealing a key mechanism of treatment failure.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Mechanistic target of rapamycin (mTOR) inhibitors are used for advanced metastatic breast cancer.
  • The mechanisms underlying sustained aggressive phenotypes or resistance to mTOR inhibition are not fully understood.

Purpose of the Study:

  • To investigate the transcriptional reprogramming driving metastasis in response to mTOR inhibition.
  • To identify key molecular drivers of resistance to mTOR-targeted therapies in breast cancer.

Main Methods:

  • Complementary studies using human tumors, cancer models, and cell lines.
  • Analysis of transcriptional changes and gene expression patterns.
  • Functional studies involving gene depletion to assess metastatic potential.

Main Results:

  • mTOR inhibition induces transcriptional reprogramming that supports metastasis.
  • EVI1 and SOX9 were identified as key drivers of this reprogramming.
  • EVI1 and SOX9 upregulate mTOR pathway components (REHB, RAPTOR) and metastasis mediators (FSCN1, SPARC).
  • EVI1 and SOX9 expression correlates with stem cell-like and metastasis signatures.
  • Depletion of EVI1 and SOX9 reduced the metastatic potential of breast cancer cells.

Conclusions:

  • Establishes a mechanistic link between resistance to mTOR inhibition and increased cancer metastatic potential.
  • Highlights the roles of EVI1 and SOX9 in mediating resistance and promoting metastasis.
  • Enhances understanding of mTOR targeting failure in breast cancer treatment.

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