CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies
| Autor: | Ryan L Powles, Carmen del Genio, Kaleigh Canfield, Jiaqi Li, Scott Bang, James DiRenzo, Maria Febbraio, Wendy A. Wells, Owen M. Wilkins, Manabu Kurokawa, Brooks R.B. Robey, Jessie Yanxiang Guo, Lajos Pusztai, Arti B. Gaur, William W. Feng, Matthew Ung, Chao Cheng, Jennifer An, William B. Kinlaw, Christos Sotiriou |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
CD36 Antigens Anabolism Receptor ErbB-2 CD36 Antineoplastic Agents Breast Neoplasms Biology Sciences de l'ingénieur medicine.disease_cause Lapatinib General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Mice 0302 clinical medicine Breast cancer Downregulation and upregulation Mice Inbred NOD HER2 Cell Line Tumor lipid metabolism medicine Animals Humans skin and connective tissue diseases Protein Kinase Inhibitors lcsh:QH301-705.5 drug resistance Microarray analysis techniques AKT Fatty Acids tyrosine kinase Cancer medicine.disease FASN MAPK 3. Good health ERK 030104 developmental biology lcsh:Biology (General) Drug Resistance Neoplasm biology.protein Cancer research Female Carcinogenesis 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Cell Reports, Vol 29, Iss 11, Pp 3405-3420.e5 (2019) Cell reports Cell reports, 29 (11 |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY Although it is established that fatty acid (FA) synthesis supports anabolic growth in cancer, the role of exogenous FA uptake remains elusive. Here we show that, during acquisition of resistance to HER2 inhibition, metabolic rewiring of breast cancer cells favors reliance on exogenous FA uptake over de novo FA synthesis. Through cDNA microarray analysis, we identify the FA transporter CD36 as a critical gene upregulated in cells with acquired resistance to the HER2 inhibitor lapatinib. Accordingly, resistant cells exhibit increased exogenous FA uptake and metabolic plasticity. Genetic or pharmacological inhibition of CD36 suppresses the growth of lapatinib-resistant but not lapatinib-sensitive cells in vitro and in vivo. Deletion of Cd36 in mammary tissues of MMTV-neu mice significantly attenuates tumorigenesis. In breast cancer patients, CD36 expression increases following anti-HER2 therapy, which correlates with a poor prognosis. Our results define CD36-mediated metabolic rewiring as an essential survival mechanism in HER2-positive breast cancer. In Brief The functional significance of lipid metabolism in cancer cells is not fully understood. Feng et al. show that the fatty acid transporter CD36 is essential for survival of breast cancer cells during anti-HER2 therapy, highlighting the role of lipid metabolism in acquired resistance to targeted therapy. Graphical Abstract |
| Databáze: | OpenAIRE |
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