IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel.
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.
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), 60 Biopolis Street, 02-01, Biopolis 138672, Singapore.
Zhen Ning
ZN
Wee
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), 60 Biopolis Street, 02-01, Biopolis 138672, Singapore.
Siti Maryam J M
SM
Yatim
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), 60 Biopolis Street, 02-01, Biopolis 138672, Singapore.
Vera K
VK
Kohlbauer
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), 60 Biopolis Street, 02-01, Biopolis 138672, Singapore.
Min
M
Feng
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), 60 Biopolis Street, 02-01, Biopolis 138672, Singapore.
Jian Yuan
JY
Goh
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), 60 Biopolis Street, 02-01, Biopolis 138672, Singapore.
Yi
Y
Bao
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), 60 Biopolis Street, 02-01, Biopolis 138672, Singapore.
Bao
B
Yi
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), 60 Biopolis Street, 02-01, Biopolis 138672, Singapore.
Puay Leng
PL
Lee
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), 60 Biopolis Street, 02-01, Biopolis 138672, Singapore.
Songjing
S
Zhang
First Affiliated Hospital, Jinan University, Guangzhou 510632, China.|Cancer Research Institute, Jinan University, Guangzhou 510632, China.
Pan Pan
PP
Wang
The Kinghorn Cancer Center, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
Elgene
E
Lim
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), 60 Biopolis Street, 02-01, Biopolis 138672, Singapore.|Cancer Science Institute, National University of Singapore, Singapore 117599, Singapore.
Wai Leong
WL
Tam
Cancer Research Institute, Jinan University, Guangzhou 510632, China.|School of Pharmacy, Jinan University, Guangzhou 510632, China.
Yu
Y
Cai
Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense 5000, Denmark.|Department of Oncology, Odense University Hospital, Odense 5000, Denmark.
Henrik J
HJ
Ditzel
Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California 90404, USA.
Dave S B
DS
Hoon
Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore.
Ern Yu
EY
Tan
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), 60 Biopolis Street, 02-01, Biopolis 138672, Singapore.|Cancer Research Institute, Jinan University, Guangzhou 510632, China.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.|Cancer and Stem Cell Biology, DUKE-NUS Graduate Medical School of Singapore, Singapore 169857, Singapore.
Qiang
Q
Yu
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage*; D010766:Phosphorylation
D000972:Antineoplastic Agents, Phytogenic; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D017239:Paclitaxel