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.

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.

Keywords: AKT; ERK; FASN; HER2; MAPK; drug resistance; lipid metabolism; tyrosine kinase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • CD36 Antigens / genetics
  • CD36 Antigens / metabolism*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Fatty Acids / metabolism*
  • Female
  • Humans
  • Lapatinib / pharmacology
  • Lapatinib / therapeutic use
  • Mice
  • Mice, Inbred NOD
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Receptor, ErbB-2 / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • CD36 Antigens
  • Fatty Acids
  • Protein Kinase Inhibitors
  • Lapatinib
  • Receptor, ErbB-2