{"doi":"10.3390/ijms241713082","title":"Targeting Oncogenic Mutant p53 and BCL-2 for Small Cell Lung Cancer Treatment","abstract":"Through a unique genomics and drug screening platform with ~800 solid tumor cell lines, we have found a subset of SCLC cell lines are hypersensitive to venetoclax, an FDA-approved inhibitor of BCL-2. SCLC-A (ASCL1 positive) and SCLC-P (POU2F3 positive), which make up almost 80% of SCLC, frequently express high levels of BCL-2. We found that a subset of SCLC-A and SCLC-P showed high BCL-2 expression but were venetoclax-resistant. In addition, most of these SCLC cell lines have TP53 missense mutations, which make a single amino acid change. These mutants not only lose wild-type (WT) p53 tumor suppressor functions, but also acquire novel cancer-promoting activities (oncogenic, gain-of-function). A recent study with oncogenic mutant (Onc)-p53 knock-in mouse models of SCLC suggests gain-of-function activity can attenuate chemotherapeutic efficacy. Based on these observations, we hypothesize that Onc-p53 confers venetoclax resistance and that simultaneous inhibition of BCL-2 and Onc-p53 induces synergistic anticancer activity in a subset of SCLC-A and SCLC-P. We show here that (1) down-regulation of Onc-p53 increases the expression of a BH3-only pro-apoptotic BIM and sensitizes to venetoclax in SCLC-P cells; (2) targeting Onc-p53 by the HSP90 inhibitor, ganetespib, increases BIM expression and sensitizes to venetoclax in SCLC-P and SCLC-A cells. Although there are currently many combination studies for venetoclax proposed, the concept of simultaneous targeting of BCL-2 and Onc-p53 by the combination of venetoclax and HSP90 inhibitors would be a promising approach for SCLC treatment.","journal":"International Journal of Molecular Sciences","year":2023,"id":358681,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"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":1109465,"name":"Alekhya Manchikalapudi","orcid":null,"position":1,"is_corresponding":false},{"id":1091285,"name":"Khanh Nguyen","orcid":"0009-0000-0688-8651","position":2,"is_corresponding":false},{"id":905888,"name":"Krista M. Dalton","orcid":"0000-0003-0027-5453","position":3,"is_corresponding":false},{"id":234822,"name":"Bin Hu","orcid":"0000-0002-0278-8466","position":4,"is_corresponding":false},{"id":344255,"name":"Jennifer E. Koblinski","orcid":"0000-0002-7156-2030","position":5,"is_corresponding":false},{"id":519468,"name":"Anthony C. Faber","orcid":"0000-0002-7246-4272","position":6,"is_corresponding":false},{"id":707886,"name":"Sumitra Deb","orcid":"0000-0002-3324-5624","position":7,"is_corresponding":false},{"id":635044,"name":"Hisashi Harada","orcid":"0000-0001-5993-1289","position":8,"is_corresponding":false},{"id":1066131,"name":"Victoria Neely","orcid":null,"position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T01:13:48.379546Z","pmid":"37685889","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":[]}