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Updated: Jan 4, 2026

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition

Molly Gale1, Yao Li1,2, Jian Cao1,3

  • 1Department of Pathology, Yale School of Medicine, New Haven, Connecticut.

Cancer Research
|November 7, 2019
PubMed

Insights

Acquired resistance to HER2-targeted therapies in breast cancer can be reversed by targeting ATP synthase. Inhibiting ATP synthase resensitizes resistant cells to trastuzumab, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Acquired resistance to HER2-targeted therapies is a significant challenge in HER2-positive breast cancer treatment.
  • New strategies are urgently needed to overcome this resistance and improve patient outcomes.

Purpose of the Study:

  • To investigate mechanisms of acquired resistance to HER2-targeted therapies.
  • To identify novel therapeutic targets and strategies to overcome resistance.

Main Methods:

  • RNA-sequencing analysis of resistant breast cancer cells.
  • Assessment of mitochondrial respiration and ATP synthase function.
  • Inhibition of ATP synthase using oligomycin A and gene knockdown.
  • In vivo studies combining ATP synthase inhibitors with trastuzumab.

Main Results:

  • Trastuzumab resistance was reversible upon culture in drug-free media.
  • Resistant cells showed increased expression of oxidative phosphorylation and ATP synthase genes.
  • Resistant cells were selectively dependent on ATP synthase function and sensitive to its inhibition.
  • Combined treatment with oligomycin A and trastuzumab led to tumor regression in vivo.

Conclusions:

  • Acquired resistance to HER2-targeted therapies involves a dependency on ATP synthase.
  • ATP synthase is a novel therapeutic target for overcoming resistance to HER2-targeted therapies.
  • Combining ATP synthase inhibitors with trastuzumab represents a promising strategy for treating resistant HER2-positive breast tumors.

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