CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies
William W. Feng,
Owen Wilkins,
Scott Bang,
Matthew Ung,
Jiaqi Li,
Jennifer An,
Carmen del Genio,
Kaleigh Canfield,
James DiRenzo,
Wendy Wells,
Arti Gaur,
R. Brooks Robey,
Jessie Yanxiang Guo,
Ryan L. Powles,
Christos Sotiriou,
Lajos Pusztai,
Maria Febbraio,
Chao Cheng,
William B. Kinlaw,
Manabu Kurokawa
Affiliations
William W. Feng
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
Owen Wilkins
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
Scott Bang
Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
Matthew Ung
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
Jiaqi Li
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
Jennifer An
Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
Carmen del Genio
Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
Kaleigh Canfield
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
James DiRenzo
Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
Wendy Wells
Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA; Norris Cotton Cancer Center, Lebanon, NH 03756, USA
Arti Gaur
Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
R. Brooks Robey
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
Jessie Yanxiang Guo
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
Ryan L. Powles
Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 05620, USA
Christos Sotiriou
Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
Lajos Pusztai
Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 05620, USA
Maria Febbraio
Department of Dentistry, University of Alberta, Edmonton, AB, Canada
Chao Cheng
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
William B. Kinlaw
Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03756, USA
Manabu Kurokawa
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; Corresponding author
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. : 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. Keywords: tyrosine kinase, HER2, FASN, drug resistance, lipid metabolism, AKT, ERK, MAPK
