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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2023-04, Vol.120 (14), p.e2220413120-e2220413120
• Main Authors: Rao, Yi, Samuels, Zachary, Carter, Lukas M, Monette, Sebastien, Panikar, Sandeep Surendra, Pereira, Patricia M R, Lewis, Jason S
• Format: Article
• Language: English
• Subjects: Animals; Binding; Biological Sciences; Cancer; Cancer therapies; Cell Line, Tumor; Cell surface; Chemotherapy; Cholesterol; Drug delivery; Drug resistance; Effectiveness; ErbB-2 protein; Feasibility studies; Gastric cancer; Growth factors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Lovastatin; Lovastatin - pharmacology; Lovastatin - therapeutic use; Lutetium; Lutetium isotopes; Metastases; Mice; Pharmaceutical Preparations; Radiation; Radiation dosage; Receptor, ErbB-2 - metabolism; Receptors; Statins; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - radiotherapy; Toxicity; Trastuzumab; Trastuzumab - pharmacology; Trastuzumab - therapeutic use; Tumors; Xenotransplantation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2220413120

Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous discoveries that statins, a class of cholesterol-lowering drugs, can enhance the cell surface-bound HER2 to achieve effective drug delivery in tumors, we proposed that the combination of statins and [ Lu]Lu-trastuzumab-based RLT can enhance the therapeutic efficacy of HER2-targeted RLT in drug-resistant gastric cancers. We demonstrate that lovastatin elevates cell surface HER2 levels and increases the tumor-absorbed radiation dose of [ Lu]Lu-DOTA-trastuzumab. Furthermore, lovastatin-modulated [ Lu]Lu-DOTA-trastuzumab RLT durably inhibits tumor growth and prolongs overall survival in mice bearing NCI-N87 gastric tumors and HER2-positive patient-derived xenografts (PDXs) of known clinical resistance to trastuzumab therapy. Statins also exhibit a radioprotective effect, reducing radiotoxicity in a mice cohort given the combination of statins and [ Lu]Lu-DOTA-trastuzumab. Since statins are commonly prescribed to patients, our results strongly support the feasibility of clinical studies that combine lovastatin with HER2-targeted RLT in HER2-postive patients and trastuzumab-resistant HER2-positive patients.