IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel

Zhen Ning Wee, Siti Maryam J. M. Yatim, Vera K Kohlbauer, Min Feng, Jian Yuan Goh, Yi Bao, Puay Leng Lee, Songjing Zhang, Pan Pan Wang, Elgene Lim, Wai Leong Tam, Yu Cai, Henrik J Ditzel, Dave S. B. Hoon, Ern Yu Tan and Qiang Yu ()
Additional contact information
Zhen Ning Wee: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research)
Siti Maryam J. M. Yatim: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research)
Vera K Kohlbauer: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research)
Min Feng: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research)
Jian Yuan Goh: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research)
Yi Bao: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research)
Puay Leng Lee: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research)
Songjing Zhang: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research)
Pan Pan Wang: First Affiliated Hospital, Jinan University
Elgene Lim: The Kinghorn Cancer Center, Garvan Institute of Medical Research
Wai Leong Tam: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research)
Yu Cai: Cancer Research Institute, Jinan University
Henrik J Ditzel: Institute of Molecular Medicine, University of Southern Denmark
Dave S. B. Hoon: John Wayne Cancer Institute, Santa Monica, California 90404, USA
Ern Yu Tan: Tan Tock Seng Hospital
Qiang Yu: Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research)

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: Abstract Metastatic tumour recurrence due to failed treatments remains a major challenge of breast cancer clinical management. Here we report that interleukin-1 receptor-associated kinase 1 (IRAK1) is overexpressed in a subset of breast cancers, in particular triple-negative breast cancer (TNBC), where it acts to drive aggressive growth, metastasis and acquired resistance to paclitaxel treatment. We show that IRAK1 overexpression confers TNBC growth advantage through NF-κB-related cytokine secretion and metastatic TNBC cells exhibit gain of IRAK1 dependency, resulting in high susceptibility to genetic and pharmacologic inhibition of IRAK1. Importantly, paclitaxel treatment induces strong IRAK1 phosphorylation, an increase in inflammatory cytokine expression, enrichment of cancer stem cells and acquired resistance to paclitaxel treatment. Pharmacologic inhibition of IRAK1 is able to reverse paclitaxel resistance by triggering massive apoptosis at least in part through inhibiting p38-MCL1 pro-survival pathway. Our study thus demonstrates IRAK1 as a promising therapeutic target for TNBC metastasis and paclitaxel resistance.

Date: 2015
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DOI: 10.1038/ncomms9746

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