Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition

Cancer Res. 2020 Feb 1;80(3):524-535. doi: 10.1158/0008-5472.CAN-18-3985. Epub 2019 Nov 5.

Abstract

Acquired resistance to HER2-targeted therapies occurs frequently in HER2+ breast tumors and new strategies for overcoming resistance are needed. Here, we report that resistance to trastuzumab is reversible, as resistant cells regained sensitivity to the drug after being cultured in drug-free media. RNA-sequencing analysis showed that cells resistant to trastuzumab or trastuzumab + pertuzumab in combination increased expression of oxidative phosphorylation pathway genes. Despite minimal changes in mitochondrial respiration, these cells exhibited increased expression of ATP synthase genes and selective dependency on ATP synthase function. Resistant cells were sensitive to inhibition of ATP synthase by oligomycin A, and knockdown of ATP5J or ATP5B, components of ATP synthase complex, rendered resistant cells responsive to a low dose of trastuzumab. Furthermore, combining ATP synthase inhibitor oligomycin A with trastuzumab led to regression of trastuzumab-resistant tumors in vivo. In conclusion, we identify a novel vulnerability of cells with acquired resistance to HER2-targeted antibody therapies and reveal a new therapeutic strategy to overcome resistance. SIGNIFICANCE: These findings implicate ATP synthase as a novel potential target for tumors resistant to HER2-targeted therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation
  • Drug Resistance, Neoplasm / drug effects*
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors*
  • Oligomycins / administration & dosage
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Trastuzumab / administration & dosage
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • ATP5F1B protein, human
  • Enzyme Inhibitors
  • Oligomycins
  • oligomycin A
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Mitochondrial Proton-Translocating ATPases
  • Trastuzumab