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Cancer Res. 2019 Nov 5. pii: canres.3985.2018. doi: 10.1158/0008-5472.CAN-18-3985. [Epub ahead of print]

Acquired resistance to HER2-targeted therapies creates vulnerability to ATP synthase inhibition.

Author information

Department of Pathology, Yale School of Medicine.
Bioinformatics R&D, Sema4.
Department of Pathology, Yale University.
Pathology, Yale School of Medicine.
School of Medicine, Oncology, Yale University.
Department of Pathology and Yale Cancer Center, Yale School of Medicine.
Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies.
Central South University, Xiangya Hospital.
Department of Pathology, Yale School of Medicine


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.

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