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Search: (WFRF:(Horvath Ildiko)) srt2:(2023) > (2023) > Dual targeting of B...

  • Valko, ZsuzsannaNational Korányi Institute for Tuberculosis and Pulmonology, Hungary,Medical University of Vienna (author)

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

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2023-03-14
  • Springer Science and Business Media LLC,2023
  • 12 s.

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:00988b4c-73f1-41d8-8909-eed3636d0547
  • https://lup.lub.lu.se/record/00988b4c-73f1-41d8-8909-eed3636d0547URI
  • https://doi.org/10.1038/s41416-023-02219-9DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • 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.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Megyesfalvi, ZsoltNational Institute of Oncology, Budapest,Medical University of Vienna,National Korányi Institute for Tuberculosis and Pulmonology, Hungary (author)
  • Schwendenwein, AnnaMedical University of Vienna (author)
  • Lang, ChristianMedical University of Vienna (author)
  • Paku, SandorSemmelweis University (author)
  • Barany, NandorNational Korányi Institute for Tuberculosis and Pulmonology, Hungary,Medical University of Vienna,Semmelweis University (author)
  • Ferencz, BenceNational Korányi Institute for Tuberculosis and Pulmonology, Hungary,National Institute of Oncology, Budapest (author)
  • Horvath-Rozsas, AnitaNational Korányi Institute for Tuberculosis and Pulmonology, Hungary (author)
  • Kovacs, IldikoNational Korányi Institute for Tuberculosis and Pulmonology, Hungary (author)
  • Schlegl, ErzsebetNational Korányi Institute for Tuberculosis and Pulmonology, Hungary (author)
  • Pozonec, VeronikaNational Institute of Oncology, Budapest (author)
  • Boettiger, KristiinaMedical University of Vienna (author)
  • Rezeli, MelindaLund 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(Swepub:lu)elma-mrl (author)
  • Marko-Varga, GyorgyLund 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(Swepub:lu)akem-gmv (author)
  • Renyi-Vamos, FerencNational Institute of Oncology, Budapest,National Korányi Institute for Tuberculosis and Pulmonology, Hungary (author)
  • Hoda, Mir AlirezaMedical University of Vienna (author)
  • Klikovits, ThomasMedical University of Vienna (author)
  • Hoetzenecker, KonradMedical University of Vienna (author)
  • Grusch, MichaelMedical University of Vienna (author)
  • Laszlo, ViktoriaNational Korányi Institute for Tuberculosis and Pulmonology, Hungary,Medical University of Vienna (author)
  • Dome, BalazsMedical University of Vienna,Lund University,National Korányi Institute for Tuberculosis and Pulmonology, Hungary,National Institute of Oncology, Budapest(Swepub:lu)ba1464do (author)
  • Schelch, KarinMedical University of Vienna (author)
  • National Korányi Institute for Tuberculosis and Pulmonology, HungaryMedical University of Vienna (creator_code:org_t)

Related titles

  • In:British Journal of Cancer: Springer Science and Business Media LLC128:10, s. 1850-18610007-09201532-1827

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