Statins enhance the efficacy of HER2-targeting radioligand therapy in drug-resistant gastric cancers Journal Article
| Authors: | Rao, Y.; Samuels, Z.; Carter, L. M.; Monette, S.; Panikar, S. S.; Pereira, P. M. R.; Lewis, J. S. |
| Article Title: | Statins enhance the efficacy of HER2-targeting radioligand therapy in drug-resistant gastric cancers |
| Abstract: | 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 [177Lu]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 [177Lu]Lu-DOTA-trastuzumab. Furthermore, lovastatin-modulated [177Lu]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 [177Lu]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. |
| Keywords: | mouse; animal; metabolism; animals; mice; epidermal growth factor receptor 2; cell line, tumor; tumor cell line; receptor, erbb-2; trastuzumab; hydroxymethylglutaryl coenzyme a reductase inhibitor; stomach neoplasms; stomach tumor; hydroxymethylglutaryl-coa reductase inhibitors; pharmaceutical preparations; mevinolin; drug; lovastatin; statins; human epidermal growth factor receptor 2 (her2); humans; human; radioligand therapy; trastuzumab-resistant cancer |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 120 |
| Issue: | 14 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2023-04-04 |
| Start Page: | e2220413120 |
| Language: | English |
| DOI: | 10.1073/pnas.2220413120 |
| PUBMED: | 36972439 |
| PROVIDER: | scopus |
| PMCID: | PMC10083538 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2023 -- Source: Scopus |
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