ArticleBritish journal of cancer2023
Dual targeting of BCL-2 and MCL-1 in the presence of BAX breaks venetoclax resistance in human small cell lung cancer.
Article in British journal of cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 40 citations in OpenAlex.
- Mechanisms of resistance in small cell lung cancer.Chinese medical journal · 2026Review
- MiR-21 Is a Novel Diagnostic and Prognostic Circulating Biomarker in Pleural Mesothelioma.Diagnostics (Basel, Switzerland) · 2026Article
- Subtype-specific dependencies and therapeutic opportunities in small cell lung cancer.Science advances · 2026Review
- Small Cell Lung Cancer Classification: Unraveling Heterogeneity to Enable Personalized Treatments.Cancer research · 2026Review
- GLMP promotes EGFR-TKI resistance by activating autophagy and RhoA pathway in non-small cell lung cancer.NPJ precision oncology · 2025Article
- Immunotherapy for small cell lung cancer: current challenges and prospects.Experimental hematology & oncology · 2025Review
- A multi-omic single-cell landscape reveals transcription and epigenetic regulatory features of t(8;21) AML.Journal of translational medicine · 2025Article
- The role of Bcl‑2 in controlling the transition between autophagy and apoptosis (Review).Molecular medicine reports · 2025Review
- Molecular Subtypes and Targeted Therapeutic Strategies in Small Cell Lung Cancer: Advances, Challenges, and Future Perspectives.Molecules (Basel, Switzerland) · 2025Review
- Unveiling the powerhouse: ASCL1-driven small cell lung cancer is characterized by higher numbers of mitochondria and enhanced oxidative phosphorylation.Cancer & metabolism · 2025Article
- Article
- Intratumoral heterogeneity and potential treatment strategies in small cell lung cancer.Frontiers in oncology · 2025Review
- Prophylactic cranial irradiation for small cell lung cancer in the era of immunotherapy and molecular subtypes.Current opinion in oncology · 2025Review
- Article
- Overcoming multi-drug resistance in SCLC: a synergistic approach with venetoclax and hydroxychloroquine targeting the lncRNA LYPLAL1-DT/BCL2/BECN1 pathway.Molecular cancer · 2024Article
- Review
- A random survival forest-based pathomics signature classifies immunotherapy prognosis and profiles TIME and genomics in ES-SCLC patients.Cancer immunology, immunotherapy : CII · 2024Article
- Emerging advances in defining the molecular and therapeutic landscape of small-cell lung cancer.Nature reviews. Clinical oncology · 2024Review
- Capivasertib reverses chemotherapy-induced esophageal cancer resistance via inhibiting Akt-associated Mcl-1 upregulation.Heliyon · 2024Article
- Article
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Authors and funding
22 authors at 4 institutions in 3 countries.
Funding
Abstract
backgroundNo targeted drugs are currently available against small cell lung cancer (SCLC). BCL-2 family members are involved in apoptosis regulation and represent therapeutic targets in many malignancies.
methodsExpression of BCL-2 family members in 27 SCLC cell lines representing all known four SCLC molecular subtypes was assessed by qPCR, Western blot and mass spectrometry-based proteomics. BCL-2 and MCL-1 inhibition (venetoclax and S63845, respectively) was assessed by MTT assay and flow cytometry and in mice bearing human SCLC tumours. Drug interactions were calculated using the Combenefit software. Ectopic BAX overexpression was achieved by expression plasmids.
resultsThe highest BCL-2 expression levels were detected in ASCL1- and POU2F3-driven SCLC cells. Although sensitivity to venetoclax was reflected by BCL-2 levels, not all cell lines responded consistently despite their high BCL-2 expression. MCL-1 overexpression and low BAX levels were both characteristic for venetoclax resistance in SCLC, whereas the expression of other BCL-2 family members did not affect therapeutic efficacy. Combination of venetoclax and S63845 resulted in significant, synergistic in vitro and in vivo anti-tumour activity and apoptosis induction in double-resistant cells; however, this was seen only in a subset with detectable BAX. In non-responding cells, ectopic BAX overexpression sensitised to venetoclax and S63845 and, furthermore, induced synergistic drug interaction.
conclusionsThe current study reveals the subtype specificity of BCL-2 expression and sheds light on the mechanism of venetoclax resistance in SCLC. Additionally, we provide preclinical evidence that combined BCL-2 and MCL-1 targeting is an effective approach to overcome venetoclax resistance in high BCL-2-expressing SCLCs with intact BAX.
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