Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition.
Molly GaleYao LiJian CaoZongzhi Z LiuMarissa A HolmbeckMeiling ZhangSabine M LangLizhen WuMariana Do CarmoSwati GuptaKeisuke AoshimaMichael P DiGiovannaDavid F SternDavid L RimmGerald S ShadelXiang ChenQin YanPublished in: Cancer research (2019)
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.
Keyphrases
- induced apoptosis
- cell cycle arrest
- epidermal growth factor receptor
- low dose
- oxidative stress
- endoplasmic reticulum stress
- emergency department
- metastatic breast cancer
- genome wide
- cancer therapy
- endothelial cells
- cell proliferation
- dna methylation
- risk assessment
- tyrosine kinase
- transcription factor
- electronic health record
- drug induced