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Cellular and Molecular Biology

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

British Journal of Cancer volume 128, pages 1850–1861 (2023)Cite this article

Subjects

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 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.

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Fig. 1: BCL-2 expression pattern poorly correlates with venetoclax resistance in SCLC cell lines.
Fig. 2: Venetoclax resistance is characterised by increased MCL-1 and decreased BAX levels.
Fig. 3: Venetoclax and S63845 synergise in a subset of SCLC cell lines in vitro and in vivo.
Fig. 4: Venetoclax and S63845 induce apoptosis in sensitive cells.
Fig. 5: BAX is required for synergistic interactions between venetoclax and S63845.

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Data availability

Data were generated by the authors and are available on request.

References

  1. Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer. 2017;17:725–37.

    Article  CAS  PubMed  Google Scholar 

  2. Schwendenwein A, Megyesfalvi Z, Barany N, Valko Z, Bugyik E, Lang C, et al. Molecular profiles of small cell lung cancer subtypes: therapeutic implications. Mol Ther Oncolytics. 2021;20:470–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Prim. 2021;7:3.

    Article  PubMed  Google Scholar 

  4. Kahnert K, Kauffmann-Guerrero D, Huber RM. SCLC-state of the art and what does the future have in store? Clin Lung Cancer. 2016;17:325–33.

    Article  PubMed  Google Scholar 

  5. Karachaliou N, Pilotto S, Lazzari C, Bria E, de Marinis F, Rosell R. Cellular and molecular biology of small cell lung cancer: an overview. Transl Lung Cancer Res. 2016;5:2–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Ganti AKP, Loo BW, Bassetti M, Blakely C, Chiang A, D’Amico TA, et al. Small Cell Lung Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19:1441–64.

    Article  CAS  PubMed  Google Scholar 

  7. Gong J, Salgia R. Managing patients with relapsed small-cell lung cancer. J Oncol Pract. 2018;14:359–66.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Esposito G, Palumbo G, Carillio G, Manzo A, Montanino A, Sforza V, et al. Immunotherapy in small cell lung cancer. Cancers. 2020;12:2522.

  9. Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220–9.

    Article  CAS  PubMed  Google Scholar 

  10. Ready N, Farago AF, de Braud F, Atmaca A, Hellmann MD, Schneider JG, et al. Third-line nivolumab monotherapy in recurrent SCLC: CheckMate 032. J Thorac Oncol. 2019;14:237–44.

    Article  CAS  PubMed  Google Scholar 

  11. Rudin CM, Poirier JT, Byers LA, Dive C, Dowlati A, George J, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019;19:289–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Drapkin BJ, Rudin CM. Advances in small-cell lung cancer (SCLC) translational research. Cold Spring Harb Perspect Med. 2021;11:a038240.

  13. Gay CM, Stewart CA, Park EM, Diao L, Groves SM, Heeke S, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39:346–60.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baine MK, Hsieh MS, Lai WV, Egger JV, Jungbluth AA, Daneshbod Y, et al. SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization. J Thorac Oncol. 2020;15:1823–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Megyesfalvi Z, Barany N, Lantos A, Valko Z, Pipek O, Lang C, et al. Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small-cell lung cancer: an international multicenter study. J Pathol. 2022;257:674–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Huang YH, Klingbeil O, He XY, Wu XS, Arun G, Lu B, et al. POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes Dev. 2018;32:915–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lochmann TL, Floros KV, Naseri M, Powell KM, Cook W, March RJ, et al. Venetoclax Is effective in small-cell lung cancers with high BCL-2 expression. Clin Cancer Res. 2018;24:360.

    Article  CAS  PubMed  Google Scholar 

  18. Schenk RL, Strasser A, Dewson G. BCL-2: long and winding path from discovery to therapeutic target. Biochem Biophys Res Commun. 2017;482:459–69.

    Article  CAS  PubMed  Google Scholar 

  19. Campbell KJ, Tait SWG. Targeting BCL-2 regulated apoptosis in cancer. Open Biol. 2018;8:180002.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Byers LA, Wang J, Nilsson MB, Fujimoto J, Saintigny P, Yordy J, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov. 2012;2:798–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Anstee NS, Bilardi RA, Ng AP, Xu Z, Robati M, Vandenberg CJ, et al. Impact of elevated anti-apoptotic MCL-1 and BCL-2 on the development and treatment of MLL-AF9 AML in mice. Cell Death Differ. 2019;26:1316–31.

    Article  CAS  PubMed  Google Scholar 

  22. Pan R, Ruvolo VR, Wei J, Konopleva M, Reed JC, Pellecchia M, et al. Inhibition of Mcl-1 with the pan-Bcl-2 family inhibitor (-)BI97D6 overcomes ABT-737 resistance in acute myeloid leukemia. Blood. 2015;126:363–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lochmann TL, Bouck YM, Faber AC. BCL-2 inhibition is a promising therapeutic strategy for small cell lung cancer. Oncoscience. 2018;5:218–9.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Roberts AW, Stilgenbauer S, Seymour JF, Huang DCS. Venetoclax in patients with previously treated chronic lymphocytic leukemia. Clin Cancer Res. 2017;23:4527–33.

    Article  CAS  PubMed  Google Scholar 

  25. Juárez-Salcedo LM, Desai V, Dalia S. Venetoclax: evidence to date and clinical potential. Drugs Context. 2019;8:212574.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ben-Ezra JM, Kornstein MJ, Grimes MM, Krystal G. Small cell carcinomas of the lung express the Bcl-2 protein. Am J Pathol. 1994;145:1036–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Tahir SK, Smith ML, Hessler P, Rapp LR, Idler KB, Park CH, et al. Potential mechanisms of resistance to venetoclax and strategies to circumvent it. BMC Cancer. 2017;17:399.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhang Q, Riley-Gillis B, Han L, Jia Y, Lodi A, Zhang H, et al. Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia. Signal Transduct Target Ther. 2022;7:51.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Szeitz B, Megyesfalvi Z, Woldmar N, Valko Z, Schwendenwein A, Barany N, et al. In-depth proteomic analysis reveals unique subtype-specific signatures in human small cell lung cancer. Clin Transl Med. 2022;12:e1060.

  30. Kuras M, Woldmar N, Kim Y, Hefner M, Malm J, Moldvay J, et al. Proteomic workflows for high-quality quantitative proteome and post-translational modification analysis of clinically relevant samples from formalin-fixed paraffin-embedded archives. J Proteome Res. 2021;20:1027–39.

    Article  CAS  PubMed  Google Scholar 

  31. Szeitz B, Woldmar N, Valko Z, Megyesfalvi Z, Barany N, Paku S, et al. Proteomic characterization of small cell lung cancer subtypes. 16th Annual US HUPO Conference; Seattle Washington, USA, 2020.

  32. Laszlo V, Valko Z, Ozsvar J, Kovacs I, Garay T, Hoda MA, et al. The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma. J Mol Med. 2019;97:231–42.

    Article  CAS  PubMed  Google Scholar 

  33. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8:e1000412.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Torok S, Rezeli M, Kelemen O, Vegvari A, Watanabe K, Sugihara Y, et al. Limited tumor tissue drug penetration contributes to primary resistance against angiogenesis inhibitors. Theranostics. 2017;7:400–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Costanzo F, Martínez Diez M, Santamaría Nuñez G, Díaz-Hernandéz JI, Genes Robles CM, Díez, et al. Promoters of ASCL1- and NEUROD1-dependent genes are specific targets of lurbinectedin in SCLC cells. EMBO Mol Med. 2022;14:e14841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Augustyn A, Borromeo M, Wang T, Fujimoto J, Shao C, Dospoy PD, et al. ASCL1 is a lineage oncogene providing therapeutic targets for high-grade neuroendocrine lung cancers. Proc Natl Acad Sci USA. 2014;111:14788–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Knelson EH, Patel SA, Sands JM. PARP inhibitors in small-cell lung cancer: rational combinations to improve responses. Cancers. 2021;13:727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Dutta C, Day T, Kopp N, van Bodegom D, Davids MS, Ryan J, et al. BCL2 suppresses PARP1 function and nonapoptotic cell death. Cancer Res. 2012;72:4193–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Punnoose EA, Leverson JD, Peale F, Boghaert ER, Belmont LD, Tan N, et al. Expression profile of BCL-2, BCL-XL, and MCL-1 predicts pharmacological response to the BCL-2 selective antagonist venetoclax in multiple myeloma models. Mol Cancer Ther. 2016;15:1132–44.

    Article  CAS  PubMed  Google Scholar 

  40. Yue X, Chen Q, He J. Combination strategies to overcome resistance to the BCL2 inhibitor venetoclax in hematologic malignancies. Cancer Cell Int. 2020;20:524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bose P, Gandhi V, Konopleva M. Pathways and mechanisms of venetoclax resistance. Leuk Lymphoma. 2017;58:1–17.

    Article  PubMed  Google Scholar 

  42. Fresquet V, Rieger M, Carolis C, García-Barchino MJ, Martinez-Climent JA. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. Blood. 2014;123:4111–9.

    Article  CAS  PubMed  Google Scholar 

  43. Yasuda Y, Ozasa H, Kim YH, Yamazoe M, Ajimizu H, Yamamoto Funazo T, et al. MCL1 inhibition is effective against a subset of small-cell lung cancer with high MCL1 and low BCL-X(L) expression. Cell Death Dis. 2020;11:177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang Y, Wang Y, Fan X, Song J, Wu H, Han J, et al. ABT-199-mediated inhibition of Bcl-2 as a potential therapeutic strategy for nasopharyngeal carcinoma. Biochem Biophys Res Commun. 2018;503:1214–20.

    Article  CAS  PubMed  Google Scholar 

  45. Moujalled DM, Pomilio G, Ghiurau C, Ivey A, Salmon J, Rijal S, et al. Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia. Leukemia. 2019;33:905–17.

    Article  CAS  PubMed  Google Scholar 

  46. Prukova D, Andera L, Nahacka Z, Karolova J, Svaton M, Klanova M, et al. Cotargeting of BCL2 with venetoclax and MCL1 with S63845 is synthetically lethal in vivo in relapsed mantle cell lymphoma. Clin Cancer Res. 2019;25:4455–65.

    Article  CAS  PubMed  Google Scholar 

  47. Seiller C, Maiga S, Touzeau C, Bellanger C, Kervoëlen C, Descamps G, et al. Dual targeting of BCL2 and MCL1 rescues myeloma cells resistant to BCL2 and MCL1 inhibitors associated with the formation of BAX/BAK hetero-complexes. Cell Death Dis. 2020;11:316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Algarín EM, Díaz-Tejedor A, Mogollón P, Hernández-García S, Corchete LA, San-Segundo L, et al. Preclinical evaluation of the simultaneous inhibition of MCL-1 and BCL-2 with the combination of S63845 and venetoclax in multiple myeloma. Haematologica. 2020;105:e116–20.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Siu KT, Huang C, Panaroni C, Mukaihara K, Fulzele K, Soucy R, et al. BCL2 blockade overcomes MCL1 resistance in multiple myeloma. Leukemia. 2019;33:2098–102.

    Article  PubMed  Google Scholar 

  50. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202–8.

    Article  CAS  PubMed  Google Scholar 

  51. Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538:477–82.

    Article  PubMed  Google Scholar 

  52. Sundararajan R, Cuconati A, Nelson D, White E. Tumor Necrosis Factor-alpha induces Bax-Bak interaction and apoptosis, which is inhibited by adenovirus E1B 19K. J Biol Chem. 2001;276:45120–7.

    Article  CAS  PubMed  Google Scholar 

  53. Debernardi J, Hollville E, Lipinski M, Wiels J, Robert A. Differential role of FL-BID and t-BID during verotoxin-1-induced apoptosis in Burkitt’s lymphoma cells. Oncogene. 2018;37:2410–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Barbara Dekan, Barbara Peter-Vörösmarty and Erzsebet Nagy for technical assistance and Nicole Woldmar and Beáta Szeitz for their help with the proteomic analyses.

Funding

KS was supported the Austrian Science Fund (FWF No. T 1062-B33) and the City of Vienna Fund for Innovative Interdisciplinary Cancer Research. BD, ZM and AR acknowledge funding from the Hungarian National Research, Development and Innovation Office (KH130356 to BD; 2020-1.1.6-JÖVŐ and TKP2021-EGA-33 to BD and ZM; FK-143751 to BD, ZM and AH-R). BD was also supported by the Austrian Science Fund (FWF I3522, FWF I3977 and I4677). ZM was supported by the UNKP-20-3 and UNKP-21-3 New National Excellence Program of the Ministry for Innovation and Technology of Hungary and by the Hungarian Respiratory Society (MPA #2020). ZM is recipient of the IASLC/ILCF Young Investigator Grant 2023. VL is a recipient of the Bolyai Research Scholarship of the Hungarian Academy of Sciences and the UNKP-19-4 New National Excellence Program of the Ministry for Innovation and Technology. MG was supported by the City of Vienna Fund for Innovative Interdisciplinary Cancer Research and the Berndorf Private Foundation. MR acknowledges funding from the Mrs. Berta Kamprad´s Cancer Foundation (FBKS-2020-22-(291)).

Author information

Author notes

  1. These authors contributed equally: Zsuzsanna Valko, Zsolt Megyesfalvi.

  2. These authors jointly supervised this work: Balazs Dome, Karin Schelch.

Authors and Affiliations

  1. Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

    Zsuzsanna Valko, Zsolt Megyesfalvi, Anna Schwendenwein, Christian Lang, Nandor Barany, Kristiina Boettiger, Mir Alireza Hoda, Thomas Klikovits, Konrad Hoetzenecker, Viktoria Laszlo, Balazs Dome & Karin Schelch

  2. National Koranyi Institute of Pulmonology, Budapest, Hungary

    Zsuzsanna Valko, Zsolt Megyesfalvi, Nandor Barany, Bence Ferencz, Anita Horvath-Rozsas, Ildiko Kovacs, Erzsebet Schlegl, Ferenc Renyi-Vamos, Viktoria Laszlo & Balazs Dome

  3. Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary

    Zsolt Megyesfalvi, Bence Ferencz, Veronika Pozonec, Ferenc Renyi-Vamos & Balazs Dome

  4. Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary

    Sandor Paku & Nandor Barany

  5. Department of Biomedical Engineering, Lund University, Lund, Sweden

    Melinda Rezeli & Gyorgy Marko-Varga

  6. Department of Thoracic Surgery, Klinik Floridsdorf, Vienna, Austria

    Thomas Klikovits

  7. Center for Cancer Research, Medical University of Vienna, Vienna, Austria

    Michael Grusch & Karin Schelch

  8. Department of Translational Medicine, Lund University, Lund, Sweden

    Balazs Dome

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  1. Zsuzsanna Valko
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Contributions

ZV was responsible for conceptualisation, data curation, formal analysis, investigation, methodology, software, visualisation, writing the original draft, review and editing. ZM was responsible for conceptualisation, data curation, formal analysis, investigation, methodology, software, resources, writing the original draft, review and editing. AS, NB, BF, AH-R, IK, and ES were responsible for data curation, writing—review and editing. CL and VP were responsible for formal analysis, writing—review and editing. SP was responsible for investigation, resources, writing—review and editing. KB was responsible for investigation, writing—review and editing. MR was responsible for data curation, software, visualisation, resources, writing—review and editing. GM-V was responsible for resources, writing—review and editing. FR-V and KH were responsible for project administration, resources, writing—review and editing. MAH, TK, and MG were responsible for project administration, writing—review and editing. VL was responsible for conceptualisation, methodology, supervision, writing—review and editing. BD was responsible for conceptualisation, investigation, methodology, project administration, resources, supervision, writing—original draft and writing—review and editing. KS was responsible for conceptualisation, data curation, investigation, methodology, project administration, software, visualisation, validation, resources, supervision, writing—original draft and writing—review and editing.

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Correspondence to Balazs Dome or Karin Schelch.

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Valko, Z., Megyesfalvi, Z., Schwendenwein, A. et al. Dual targeting of BCL-2 and MCL-1 in the presence of BAX breaks venetoclax resistance in human small cell lung cancer. Br J Cancer 128, 1850–1861 (2023). https://doi.org/10.1038/s41416-023-02219-9

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