{"doi":"10.1101/2022.09.12.507616","title":"Co-targeting BCL-X <sub>L</sub> and MCL-1 with DT2216 and AZD8055 synergistically inhibits small-cell lung cancer growth without causing on-target toxicities in mice","abstract":"ABSTRACT Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. The dismal prognosis in SCLC is in part associated with an upregulation of BCL-2 family anti-apoptotic proteins, including BCL-X L and MCL-1. Unfortunately, the currently available inhibitors of BCL-2 family anti-apoptotic proteins, except BCL-2 inhibitors, are not clinically relevant because of various on-target toxicities. We, therefore, aimed to develop an effective and safe strategy targeting these anti-apoptotic proteins with DT2216 (our platelet-sparing BCL-X L degrader) and AZD8055 (an mTOR inhibitor) to avoid associated on-target toxicities while synergistically optimizing tumor response. Through BH3 mimetic screening, we identified a subset of SCLC cell lines that is co-dependent on BCL-X L and MCL-1. After screening inhibitors of selected tumorigenic pathways, we found that AZD8055 selectively downregulates MCL-1 in SCLC cells and its combination with DT2216 synergistically killed BCL-X L /MCL-1 co-dependent SCLC cells, but not normal cells. Mechanistically, the combination caused BCL-X L degradation and suppression of MCL1 expression, and thus disrupted MCL-1 interaction with BIM leading to an enhanced apoptotic induction. In vivo , DT2216+AZD8055 combination significantly inhibited the growth of cell line-derived and patient-derived xenografts and reduced tumor burden accompanied with extended survival in a genetically-engineered mouse (GEM) model of SCLC without causing significant thrombocytopenia or other normal tissue injury. Thus, these preclinical findings lay a strong foundation for future clinical studies to test DT2216+mTOR inhibitor combination in a subset of SCLC patients whose tumors are co-driven by BCL-X L and MCL-1.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":311455,"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":0.9564,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1007673,"name":"Patrick Kellish","orcid":"0000-0002-8675-3358","position":1,"is_corresponding":false},{"id":724211,"name":"Nick Connis","orcid":"0000-0001-5725-0674","position":2,"is_corresponding":false},{"id":237875,"name":"Dinesh Thummuri","orcid":"0000-0002-6027-0999","position":3,"is_corresponding":false},{"id":239228,"name":"J Wiegand","orcid":null,"position":4,"is_corresponding":false},{"id":237867,"name":"Peiyi Zhang","orcid":"0000-0003-0207-1112","position":5,"is_corresponding":false},{"id":237864,"name":"Xuan Zhang","orcid":"0000-0001-6062-6708","position":6,"is_corresponding":false},{"id":239229,"name":"Vivekananda Budamagunta","orcid":null,"position":7,"is_corresponding":false},{"id":628408,"name":"Nan Hua","orcid":"0000-0002-2152-1273","position":8,"is_corresponding":false},{"id":226413,"name":"Yang Yang","orcid":"0000-0003-0428-5480","position":9,"is_corresponding":false},{"id":631001,"name":"Umasankar De","orcid":"0000-0003-4478-791X","position":10,"is_corresponding":false},{"id":481186,"name":"Lingtao Jin","orcid":"0009-0005-8106-3250","position":11,"is_corresponding":false},{"id":273483,"name":"Weizhou Zhang","orcid":"0000-0002-8236-0346","position":12,"is_corresponding":false},{"id":237880,"name":"Guangrong Zheng","orcid":"0000-0002-8106-6663","position":13,"is_corresponding":false},{"id":240060,"name":"Robert Hromas","orcid":"0000-0002-1916-6276","position":14,"is_corresponding":false},{"id":251309,"name":"Christine L. Hann","orcid":"0000-0002-1467-5557","position":15,"is_corresponding":false},{"id":859267,"name":"Maria Zajac‐Kaye","orcid":"0000-0001-8804-9076","position":16,"is_corresponding":false},{"id":35279,"name":"Frederic J. Kaye","orcid":"0000-0001-8565-1854","position":17,"is_corresponding":false},{"id":237881,"name":"Daohong Zhou","orcid":"0000-0002-2400-6461","position":18,"is_corresponding":false},{"id":237869,"name":"Sajid Khan","orcid":"0000-0003-1331-8846","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T00:33:28.480200Z","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":[]}