Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Valko, Zsuzsanna ; Megyesfalvi, Zsolt ; Schwendenwein, Anna ; Lang, Christian ; Paku, Sandor ; Barany, Nandor ; Ferencz, Bence ; Horvath-Rozsas, Anita ; Kovacs, Ildiko and Schlegl, Erzsebet , et al. (2023) In British Journal of Cancer 128(10). p.1850-1861
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
British Journal of Cancer
volume
128
issue
10
pages
12 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:36918717
  • scopus:85149864068
ISSN
0007-0920
DOI
10.1038/s41416-023-02219-9
language
English
LU publication?
yes
id
00988b4c-73f1-41d8-8909-eed3636d0547
date added to LUP
2023-05-15 12:13:40
date last changed
2024-06-29 04:03:22
@article{00988b4c-73f1-41d8-8909-eed3636d0547,
  abstract     = {{<p>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.</p>}},
  author       = {{Valko, Zsuzsanna and Megyesfalvi, Zsolt and Schwendenwein, Anna and Lang, Christian and Paku, Sandor and Barany, Nandor and Ferencz, Bence and Horvath-Rozsas, Anita and Kovacs, Ildiko and Schlegl, Erzsebet and Pozonec, Veronika and Boettiger, Kristiina and Rezeli, Melinda and Marko-Varga, Gyorgy and Renyi-Vamos, Ferenc and Hoda, Mir Alireza and Klikovits, Thomas and Hoetzenecker, Konrad and Grusch, Michael and Laszlo, Viktoria and Dome, Balazs and Schelch, Karin}},
  issn         = {{0007-0920}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{1850--1861}},
  publisher    = {{Nature Publishing Group}},
  series       = {{British Journal of Cancer}},
  title        = {{Dual targeting of BCL-2 and MCL-1 in the presence of BAX breaks venetoclax resistance in human small cell lung cancer}},
  url          = {{http://dx.doi.org/10.1038/s41416-023-02219-9}},
  doi          = {{10.1038/s41416-023-02219-9}},
  volume       = {{128}},
  year         = {{2023}},
}