{"doi":"10.3390/cancers17152583","title":"The Fanconi Anemia Pathway Inhibits mTOR Signaling and Prevents Accelerated Translation in Head and Neck Cancer Cells","abstract":"Background/Objectives: The Fanconi anemia (FA) pathway is essential for the repair of DNA interstrand crosslinks and maintenance of genomic stability. Germline loss of FA pathway function in the inherited Fanconi anemia syndrome leads to increased DNA damage and a range of clinical phenotypes, including a heightened risk of head and neck squamous cell carcinoma (HNSCC). Non-synonymous FA gene mutations are also observed in up to 20% of sporadic HNSCCs. The mechanistic target of rapamycin (mTOR) is known to stimulate cell growth, anabolic metabolism including protein synthesis, and survival following genotoxic stress. Methods/Results: Here, we demonstrate that FA− deficient (FA−) HNSCC cells exhibit elevated intracellular amino acid levels, increased total protein content, and an increase in protein synthesis indicative of enhanced translation. These changes are accompanied by hyperactivation of the mTOR effectors translation initiation factor 4E Binding Protein 1 (4E-BP1) and ribosomal protein S6. Treatment with the mTOR inhibitor rapamycin reduced the phosphorylation of these targets and blocked translation specifically in FA− cells but not in their isogenic FA− proficient (FA+) counterparts. Rapamycin-mediated mTOR inhibition sensitized FA− but not FA+ cells to rapamycin under nutrient stress, supporting a therapeutic metabolism-based vulnerability in FA− cancer cells. Conclusions: These findings uncover a novel role for the FA pathway in suppressing mTOR signaling and identify mTOR inhibition as a potential strategy for targeting FA− HNSCCs.","journal":"Cancers","year":2025,"id":545860,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9563,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":232990,"name":"Sara Vicente-Muñoz","orcid":"0000-0003-4454-8900","position":1,"is_corresponding":false},{"id":1291494,"name":"Khyati Y. Mehta","orcid":"0000-0002-2613-1362","position":2,"is_corresponding":false},{"id":765391,"name":"Cosette M. Rivera‐Cruz","orcid":"0000-0001-5487-0106","position":3,"is_corresponding":false},{"id":705206,"name":"Xueheng Zhao","orcid":"0000-0002-4156-3294","position":4,"is_corresponding":false},{"id":284237,"name":"Lindsey E. Romick‐Rosendale","orcid":"0000-0002-7252-1193","position":5,"is_corresponding":false},{"id":526807,"name":"Kenneth D.R. Setchell","orcid":"0000-0001-9147-0136","position":6,"is_corresponding":false},{"id":320795,"name":"Adam Lane","orcid":"0000-0002-5522-8112","position":7,"is_corresponding":false},{"id":424829,"name":"Susanne I. Wells","orcid":"0000-0002-7234-676X","position":8,"is_corresponding":false},{"id":1437570,"name":"Bianca Ruffolo","orcid":null,"position":0,"is_corresponding":true}],"reference_count":98,"raw_metadata":null,"created_at":"2026-07-19T02:53:27.751050Z","pmid":"40805278","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":[]}