Dual targeting of BCL-2 and MCL-1 in the presence of BAX breaks venetoclax resistance in human small cell lung cancer.

Animals Humans Mice Antineoplastic Agents / pharmacology Apoptosis bcl-2-Associated X Protein / genetics Bridged Bicyclo Compounds, Heterocyclic / pharmacology Cell Line, Tumor Drug Resistance, Neoplasm / drug effects Lung Neoplasms / drug therapy Myeloid Cell Leukemia Sequence 1 Protein / drug effects Proto-Oncogene Proteins c-bcl-2 / drug effects Small Cell Lung Carcinoma / drug therapy

Journal

British journal of cancer

ISSN: 1532-1827

Titre abrégé: Br J Cancer

Pays: England

ID NLM: 0370635

Informations de publication

Date de publication:
05 2023

Historique:

received: 05 10 2022

accepted: 24 02 2023

revised: 20 02 2023

pmc-release: 14 03 2024

medline: 1 5 2023

pubmed: 16 3 2023

entrez: 15 3 2023

Statut: ppublish

Résumé

No 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. Expression 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. The 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. The 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.

Sections du résumé

BACKGROUND

No 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.

METHODS

Expression 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.

RESULTS

The 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.

CONCLUSIONS

The 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.

Identifiants

DOI: 10.1038/s41416-023-02219-9 PMID: 36918717 PMC: PMC10147697

pubmed: 36918717

doi: 10.1038/s41416-023-02219-9

pii: 10.1038/s41416-023-02219-9

pmc: PMC10147697

doi:

Substances chimiques

Antineoplastic Agents 0

bcl-2-Associated X Protein 0

Bridged Bicyclo Compounds, Heterocyclic 0

Myeloid Cell Leukemia Sequence 1 Protein 0

Proto-Oncogene Proteins c-bcl-2 0

S63845 0

venetoclax N54AIC43PW

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1850-1861

Informations de copyright

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