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

Susan E. Logue, Eoghan P. McGrath, Patricia Cleary, Stephanie Greene, Katarzyna Mnich, Aitor Almanza, Eric Chevet, Róisín M. Dwyer, Anup Oommen, Patrick Legembre, Florence Godey, Emma C. Madden, Brian Leuzzi, Joanna Obacz, Qingping Zeng, John B. Patterson, Richard Jäger, Adrienne M. Gorman and Afshin Samali ()
Additional contact information
Susan E. Logue: National University of Ireland Galway
Eoghan P. McGrath: National University of Ireland Galway
Patricia Cleary: National University of Ireland Galway
Stephanie Greene: Fosun Orinove PharmaTech Inc.
Katarzyna Mnich: National University of Ireland Galway
Aitor Almanza: National University of Ireland Galway
Eric Chevet: Université de Rennes 1
Róisín M. Dwyer: National University of Ireland Galway
Anup Oommen: National University of Ireland Galway
Patrick Legembre: Université de Rennes 1
Florence Godey: Université de Rennes 1
Emma C. Madden: National University of Ireland Galway
Brian Leuzzi: National University of Ireland Galway
Joanna Obacz: Université de Rennes 1
Qingping Zeng: Fosun Orinove PharmaTech Inc.
John B. Patterson: Fosun Orinove PharmaTech Inc.
Richard Jäger: University of Applied Sciences, Department of Natural Sciences
Adrienne M. Gorman: National University of Ireland Galway
Afshin Samali: National University of Ireland Galway

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.

Date: 2018
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DOI: 10.1038/s41467-018-05763-8

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