CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies

Cell Rep. 2019 Dec 10;29(11):3405-3420.e5. doi: 10.1016/j.celrep.2019.11.008. | PubMed

William W Feng¹, Owen Wilkins², Scott Bang³, Matthew Ung⁴, Jiaqi Li⁴, Jennifer An⁵, Carmen Del Genio⁵, Kaleigh Canfield⁴, James DiRenzo⁴, Wendy Wells⁶, Arti Gaur⁵, R Brooks Robey⁷, Jessie Yanxiang Guo⁸, Ryan L Powles⁹, Christos Sotiriou¹⁰, Lajos Pusztai⁹, Maria Febbraio¹¹, Chao Cheng¹², William B Kinlaw¹³, Manabu Kurokawa¹⁴

1. Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Department of Biological Sciences, Kent State University, Kent, OH 44242, USA.
2. Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
3. Department of Biological Sciences, Kent State University, Kent, OH 44242, USA.
4. Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
5. Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
6. Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA; Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
7. Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Department of Medical Education, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; White River Junction Veterans Affairs Medical Center, White River Junction, VT 05009, USA.
8. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
9. Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 05620, USA.
10. Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
11. Department of Dentistry, University of Alberta, Edmonton, AB, Canada.
12. Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03756, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
13. Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
14. Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Department of Biological Sciences, Kent State University, Kent, OH 44242, USA. Electronic address: mkurokaw@kent.edu.

Abstract

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.

Presented By William Feng