{"doi":"10.1101/2024.02.22.581532","title":"Oncogenic Mutant p53 Sensitizes Non-Small Cell Lung Cancer Cells to Proteasome Inhibition via Oxidative Stress-Dependent Induction of Mitochondrial Apoptosis","abstract":"Abstract Non-small cell lung cancer (NSCLC) cells with oncogenic mutant p53 alleles (Onc-p53) exhibit significantly higher levels of proteasome activity, indicating that Onc-p53 induces proteotoxic stress which may be leveraged as a therapeutic vulnerability. Proteasome inhibitors (PIs), such as bortezomib (BTZ), can induce toxic levels of oxidative stress in cancer cells and thus we investigated whether PIs exhibit preferential cytotoxicity in Onc-p53 NSCLC cells. Indeed, BTZ and other PIs exhibited the IC 50 6-7-fold lower in Onc-p53 cells vs. wild-type (WT) p53 cells. BTZ cytotoxic effects in Onc-p53 cells were nearly completely rescued by antioxidants such as N-acetyl cysteine, indicating that oxidative stress is the critical driver of BTZ-dependent cytotoxic effects in Onc-p53 cells. Importantly, we observed oxidative stress-dependent transcriptional induction of the pro-apoptotic NOXA with downstream cleaved caspase-3, consistent with apoptotic cell death in Onc-p53 but not in WT p53 cells treated with BTZ, and BTZ-generated oxidative stress was linked to nuclear translocation of NRF2 and transcriptional activation of ATF3, which in turn was required for NOXA induction. Validating BTZ’s translational potential in Onc-p53 NSCLC, BTZ and carboplatin or the BH3-mimetic navitoclax were synergistically cytotoxic in Onc-p53 but not WT p53 cells in vitro, and BTZ effectively limited growth of Onc-p53 NSCLC xenografts when combined with either carboplatin or navitoclax in vivo . Our data therefore support further investigation of the therapeutic utility of PIs combined with carboplatin or BH3-mimetics in Onc-p53 human NSCLC as novel therapeutic strategies. Significance Non-small cell lung cancer (NSCLC) is the leading cause of cancer death due, in part, to a lack of active therapies in advanced disease. We demonstrate that proteasome inhibitor/BH3-mimetic combination therapy is an active precision therapy in NSCLC cells and tumors expressing oncogenic mutant p53 alleles (Onc-p53).","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":494639,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.957,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1066131,"name":"Victoria Neely","orcid":null,"position":1,"is_corresponding":false},{"id":398868,"name":"Boxiao Ding","orcid":null,"position":2,"is_corresponding":false},{"id":1265579,"name":"Eziafa Oduah","orcid":"0000-0001-8517-6360","position":3,"is_corresponding":false},{"id":1341334,"name":"V. K.-H. Lam","orcid":null,"position":4,"is_corresponding":false},{"id":234822,"name":"Bin Hu","orcid":"0000-0002-0278-8466","position":5,"is_corresponding":false},{"id":344255,"name":"Jennifer E. Koblinski","orcid":"0000-0002-7156-2030","position":6,"is_corresponding":false},{"id":327372,"name":"B E Windle","orcid":null,"position":7,"is_corresponding":false},{"id":708387,"name":"Swati Palit Deb","orcid":null,"position":8,"is_corresponding":false},{"id":707886,"name":"Sumitra Deb","orcid":"0000-0002-3324-5624","position":9,"is_corresponding":false},{"id":456209,"name":"Senthil K. Radhakrishnan","orcid":"0000-0002-5211-9498","position":10,"is_corresponding":false},{"id":635044,"name":"Hisashi Harada","orcid":"0000-0001-5993-1289","position":11,"is_corresponding":false},{"id":397946,"name":"Steven R. Grossman","orcid":"0009-0003-4692-6925","position":12,"is_corresponding":false},{"id":1138488,"name":"Kranthi Kumar Chougoni","orcid":"0000-0003-4102-8723","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:09:11.736910Z","pmid":null,"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":[]}