Statins enhance the efficacy of HER2-targeting radioligand therapy in drug-resistant gastric cancers

Significance Trastuzumab and trastuzumab-based drug resistance is a clinical challenge in recurrent and primary metastatic gastric cancers. Not all tumors respond to trastuzumab-based therapy and resistance is observed in the ones that show initial response. Because trastuzumab-based systemic endoradiotherapy requires only the extramembrane domain binding of membrane-bound Human epidermal growth factor receptor 2 (HER2) receptors, HER2-targeting radioimmunotherapy can bypass any resistance mechanisms that occur downstream of HER2 binding. We repurposed statins to enhance cell-surface HER2 availability in ways that increase tumor-to-nontarget–organ absorbed dose ratios and enhance efficacy in tumors resistant to conventional trastuzumab therapy. Ultimately, statins improve the efficacy of systemic radioimmunotherapy in drug-resistant HER2+ EG patients.

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