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Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy

Susan E Logue1,2, Eoghan P McGrath1,2, Patricia Cleary1,2

  • 1Apoptosis Research Centre, National University of Ireland Galway, University Road, Galway, H91 TK33, Ireland.

Nature Communications
|August 17, 2018
PubMed

Insights

Triple-negative breast cancer (TNBC) cells rely on IRE1 RNase activity for pro-tumorigenic factor production. Inhibiting IRE1 enhances paclitaxel

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to the absence of targeted therapies and a poorer prognosis.
  • The endoplasmic reticulum (ER) stress sensor, IRE1, plays a dual role in cellular stress responses, mediating survival under mild stress and promoting cell death under severe stress.

Purpose of the Study:

  • To investigate the role of IRE1 RNase activity in TNBC pathogenesis and its potential as a therapeutic target.
  • To determine if IRE1 activity contributes to the expansion of tumor-initiating cells induced by chemotherapy.

Main Methods:

  • Analysis of basal pro-tumorigenic factor production in TNBC cells.
  • Assessment of IRE1 RNase activity modulation by paclitaxel.
  • Evaluation of IRE1 inhibition in combination with paclitaxel in a TNBC xenograft mouse model.

Main Results:

  • Constitutive IRE1 RNase activity in TNBC cells drives the production of pro-tumorigenic factors including IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2.
  • Paclitaxel treatment enhances IRE1 RNase activity, contributing to the expansion of tumor-initiating cells.
  • Inhibition of IRE1 RNase activity potentiates paclitaxel's tumor suppressive effects and delays relapse in vivo.

Conclusions:

  • IRE1 RNase activity is a critical mediator of pro-tumorigenic signaling in TNBC.
  • Targeting IRE1 RNase activity represents a promising strategy to enhance the efficacy of existing chemotherapies like paclitaxel for TNBC.
  • Combining IRE1 inhibition with chemotherapy could overcome therapeutic resistance and improve patient outcomes in TNBC.

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