Journal Article

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

Dwyer, Róisín M., Jäger, Richard, Cleary, Patricia, Zeng, Qingping, Mnich, Katarzyna, Gorman, Adrienne M., Logue, Susan E., Samali, Afshin, Chevet, Eric, Madden, Emma C., Almanza, Aitor, Legembre, Patrick, Greene, Stephanie, Obacz, Joanna, Oommen, Anup, Godey, Florence, Patterson, John B., Leuzzi, Brian, McGrath, Eoghan P.

2018

Overview

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. IRE1/XBP-1 activation has a major role in Triple negative breast cancer (TNBC). Here, the authors show that inhibition of IRE1’s RNase activity attenuates autocrine and paracrine signaling of pro-tumorigenic cytokines and synergizes with paclitaxel to confer potent anti-tumor effects in TNBC.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/105 / 13/106 / 13/2 / 13/51 / 13/89 / 13/95 / 38/39 / 38/61 / 42 / 631/67/71 / 692/4028/67/1347 / Animals / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Breast cancer / Cancer / Cell death / Cell Line / Cell Line, Tumor / Chemotherapy / Endoplasmic reticulum / Endoribonucleases - antagonists & inhibitors / Endoribonucleases - genetics / Endoribonucleases - metabolism / Enzyme Inhibitors - administration & dosage / Female / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Granulocyte-macrophage colony-stimulating factor / HEK293 Cells / Humanities and Social Sciences / Humans / Interleukin 6 / Interleukin 8 / Life Sciences / Mice, Nude / multidisciplinary / Paclitaxel / Paclitaxel - administration & dosage / Pharmaceutical sciences / Pharmacology / Protein Serine-Threonine Kinases - antagonists & inhibitors / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Ribonuclease / RNA Interference / Science / Science (multidisciplinary) / Secretome / Stresses / Therapeutic applications / Triple Negative Breast Neoplasms - drug therapy / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - metabolism / Tumor suppression / Tumors / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation