{"doi":"10.1073/pnas.2220413120","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 [ 177 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 [ 177 Lu]Lu-DOTA-trastuzumab. Furthermore, lovastatin-modulated [ 177 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 [ 177 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.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":331965,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":751471,"name":"Zachary V. Samuels","orcid":"0000-0001-6639-5402","position":1,"is_corresponding":false},{"id":268011,"name":"Lukas M. Carter","orcid":"0000-0003-4848-4190","position":2,"is_corresponding":false},{"id":467193,"name":"Sébastien Monette","orcid":"0000-0003-2841-6887","position":3,"is_corresponding":false},{"id":869087,"name":"Sandeep Surendra Panikar","orcid":"0000-0002-1275-1069","position":4,"is_corresponding":false},{"id":320708,"name":"Patrícia M. R. Pereira","orcid":"0000-0002-4772-9339","position":5,"is_corresponding":false},{"id":235762,"name":"Jason S. Lewis","orcid":"0000-0001-7065-4534","position":6,"is_corresponding":false},{"id":694227,"name":"Yi Rao","orcid":"0000-0001-9858-1410","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T01:09:25.015646Z","pmid":"36972439","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}