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

Valko, Zsuzsanna (författare)
Medical University of Vienna,National Korányi Institute for Tuberculosis and Pulmonology, Hungary
Megyesfalvi, Zsolt (författare)
National Institute of Oncology, Budapest,Medical University of Vienna,National Korányi Institute for Tuberculosis and Pulmonology, Hungary
Schwendenwein, Anna (författare)
Medical University of Vienna
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Lang, Christian (författare)
Medical University of Vienna
Paku, Sandor (författare)
Semmelweis University
Barany, Nandor (författare)
Semmelweis University,National Korányi Institute for Tuberculosis and Pulmonology, Hungary,Medical University of Vienna
Ferencz, Bence (författare)
National Institute of Oncology, Budapest,National Korányi Institute for Tuberculosis and Pulmonology, Hungary
Horvath-Rozsas, Anita (författare)
National Korányi Institute for Tuberculosis and Pulmonology, Hungary
Kovacs, Ildiko (författare)
National Korányi Institute for Tuberculosis and Pulmonology, Hungary
Schlegl, Erzsebet (författare)
National Korányi Institute for Tuberculosis and Pulmonology, Hungary
Pozonec, Veronika (författare)
National Institute of Oncology, Budapest
Boettiger, Kristiina (författare)
Medical University of Vienna
Rezeli, Melinda (författare)
Lund University,Lunds universitet,Universitetsbiblioteket,Bibliotek,Avdelningen för Biomedicinsk teknik,Institutionen för biomedicinsk teknik,Institutioner vid LTH,Lunds Tekniska Högskola,BioMS,Forskargrupper vid Lunds universitet,Clinical Protein Science and Imaging,Lund University Library,Library,Department of Biomedical Engineering,Departments at LTH,Faculty of Engineering, LTH,Lund University Research Groups
Marko-Varga, Gyorgy (författare)
Lund University,Lunds universitet,Avdelningen för Biomedicinsk teknik,Institutionen för biomedicinsk teknik,Institutioner vid LTH,Lunds Tekniska Högskola,Clinical Protein Science and Imaging,Forskargrupper vid Lunds universitet,Department of Biomedical Engineering,Departments at LTH,Faculty of Engineering, LTH,Lund University Research Groups
Renyi-Vamos, Ferenc (författare)
National Institute of Oncology, Budapest,National Korányi Institute for Tuberculosis and Pulmonology, Hungary
Hoda, Mir Alireza (författare)
Medical University of Vienna
Klikovits, Thomas (författare)
Medical University of Vienna
Hoetzenecker, Konrad (författare)
Medical University of Vienna
Grusch, Michael (författare)
Medical University of Vienna
Laszlo, Viktoria (författare)
Medical University of Vienna,National Korányi Institute for Tuberculosis and Pulmonology, Hungary
Dome, Balazs (författare)
Lund University,National Institute of Oncology, Budapest,National Korányi Institute for Tuberculosis and Pulmonology, Hungary,Medical University of Vienna
Schelch, Karin (författare)
Medical University of Vienna
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 (creator_code:org_t)
2023-03-14
2023
Engelska 12 s.
Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 128:10, s. 1850-1861
Relaterad länk:
http://dx.doi.org/10...
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https://lup.lub.lu.s...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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