Acquired resistance to HER2-targeted therapies occurs frequently in HER2 þ 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 HER2targeted 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.
Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the features of this landscape remain poorly understood and cannot be revealed by human cancer genotyping alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. The resulting fitness landscape is rugged (the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context), shows no evidence of diminishing-returns epistasis within variants of the same oncogene, and is inconsistent with expectations of a simple linear signaling relationship among these three oncogenes. Our findings suggest that tumor suppressor effects are strongly context-specific, which limits the set of evolutionary paths that can be taken through the fitness landscape.
<p>Supplementary Figure 1: Generation and characterization of resistant cell pools. Supplementary Figure 2: Copy number assessment of receptor tyrosine kinases in resistant cell pools. Supplementary Figure 3: Trastuzumab resistance is reversible. Supplementary Figure 4: Drug resistant cells are more sensitive to OXPHOS inhibitors than parental cells. Supplementary Figure 5: Drug resistant cells have similar mitochondrial DNA copy numbers and ATP levels as the parental cells. Supplementary Figure 6: Glycolysis in parental BT474 versus trastuzumab resistant cells. Supplementary Figure 7: ATP synthase gene expression in BT474, SKBR3 cells and their derived trastuzumab-resistant cells. Supplementary Figure 8: Cumulative survival of breast cancer (all, basal, luminal) patients with patients divided in half by ATP5B (left) or ATP5A1 (right) mRNA level. Supplementary Figure 9: ATP5B protein expression correlation with survival in HER2+, trastuzumab treated patients from HeCOG 10/05. Supplementary Figure 10: ATP5B is required for the maintenance of resistance. Supplementary Figure 11: BT-TR2 tumor morphology and proliferation. Supplementary Table 1: Sequences of primers and plasmid inserts. Supplementary Methods Supplementary References</p>
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