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LMTK3 confers chemo-resistance in breast cancer

Authors
  • Stebbing, Justin1
  • Shah, Kalpit2
  • Lit, Lei Cheng1, 3
  • Gagliano, Teresa4
  • Ditsiou, Angeliki4
  • Wang, Tingting5
  • Wendler, Franz4
  • Simon, Thomas4
  • Szabó, Krisztina Sára4
  • O’Hanlon, Timothy6
  • Dean, Michael2
  • Roslani, April Camilla7
  • Cheah, Swee Hung3
  • Lee, Soo-Chin5
  • Giamas, Georgios4
  • 1 Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Department of Surgery and Cancer, Du Cane Road, London, W12 ONN, UK , London (United Kingdom)
  • 2 National Institutes of Health (NIH), Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), Bethesda, MD, 20892, USA , Bethesda (United States)
  • 3 University of Malaya, Department of Physiology, Faculty of Medicine, Kuala Lumpur, 50603, Malaysia , Kuala Lumpur (Malaysia)
  • 4 University of Sussex, School of Life Sciences, Department of Biochemistry and Biomedicine, Brighton, BN1 9QG, UK , Brighton (United Kingdom)
  • 5 Centre for Life Sciences, Cancer Science Institute of Singapore, 28 Medical Drive, #02-15, Singapore, Singapore , Singapore (Singapore)
  • 6 Leidos Biomedical Research Inc., Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, 20892, USA , Bethesda (United States)
  • 7 University of Malaya, Department of Surgery, Faculty of Medicine, Kuala Lumpur, 50603, Malaysia , Kuala Lumpur (Malaysia)
Type
Published Article
Journal
Oncogene
Publisher
Nature Publishing Group UK
Publication Date
Mar 15, 2018
Volume
37
Issue
23
Pages
3113–3130
Identifiers
DOI: 10.1038/s41388-018-0197-0
Source
Springer Nature
License
Green

Abstract

Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment. In a mouse model we showed that ectopic overexpression of LMTK3 decreases the efficacy of doxorubicin in reducing tumor growth. Interestingly, breast cancer cells overexpressing LMTK3 delayed the generation of double strand breaks (DSBs) after exposure to doxorubicin, as measured by the formation of γH2AX foci. This effect was at least partly mediated by decreased activity of ataxia-telangiectasia mutated kinase (ATM) as indicated by its reduced phosphorylation levels. In addition, our RNA-seq analyses showed that doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels. Furthermore, these genes were found to promote DNA repair, cell viability and tumorigenesis processes / pathways in LMTK3-overexpressing MCF7 cells. In human cancers, immunohistochemistry staining of LMTK3 in pre- and post-chemotherapy breast tumor pairs from four separate clinical cohorts revealed a significant increase of LMTK3 following both doxorubicin and docetaxel based chemotherapy. In aggregate, our findings show for the first time a contribution of LMTK3 in cytotoxic drug resistance in breast cancer.

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