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

Molly Gale, Yao Li, Jian Cao, Zongzhi Z. Liu, Marissa A. Holmbeck, Meiling Zhang, Sabine M. Lang, Lizhen Wu, Mariana Do Carmo, Swati Gupta, Keisuke Aoshima, Michael P. DiGiovanna, David F. Stern, David L. Rimm, Gerald S. Shadel, Xiang Chen, Qin Yan

Research output: Contribution to journalArticle

Abstract

Acquired resistance to HER2-targeted therapies occurs frequently in HER2þ 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 þ 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.

Original languageEnglish (US)
Pages (from-to)524-535
Number of pages12
JournalCancer Research
Volume80
Issue number3
DOIs
StatePublished - Feb 1 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Gale, M., Li, Y., Cao, J., Liu, Z. Z., Holmbeck, M. A., Zhang, M., Lang, S. M., Wu, L., Carmo, M. D., Gupta, S., Aoshima, K., DiGiovanna, M. P., Stern, D. F., Rimm, D. L., Shadel, G. S., Chen, X., & Yan, Q. (2020). Acquired resistance to HER2-targeted therapies creates vulnerability to ATP synthase inhibition. Cancer Research, 80(3), 524-535. https://doi.org/10.1158/0008-5472.CAN-18-3985