PhD Scientific Days 2024
Budapest, 9-10 July 2024
Pathological and Oncological Sciences III.
Investigation of Novel Therapeutic Targets in Small Cell Lung Cancer – Dual Inhibition of BCL-2 and MCL-1
Előadó neve
Dr. Požonec, Veronika
Neptun code
ib0xr7
Előadó munkahelye
National Institue of Oncology
Előadó telefonszáma
06309631044
Előadó e-mail címe
pozonec.veronika@oncol.hu
Az előadás címe
Investigation of Novel Therapeutic Targets in Small Cell Lung Cancer – Dual Inhibition of BCL-2 and MCL-1
Szerző(k) neve és munkahelye
Veronika Pozonec1,2, Zsolt Megyesfalvi1,3,4, Zsuzsanna Valko4,5, Anna Schwendenwein5, Christian Lang5, Sandor Paku6, Nandor Barany4,5,6, Bence Ferencz1,4, Erzsebet Schlegl4, Kristiina Boettiger5, Melinda Rezeli7, Gyorgy Marko-Varga7, Ferenc Renyi-Vamos1,4, Mir Alireza Hoda5, Thomas Klikovits5,8, Konrad Hoetzenecker5, Michael Grusch9, Viktoria Laszlo4,5, Balazs Dome1,4,5,10, Karin Schelch5,9
1: Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary
2: Department of Head and Neck Oncology, Multidisciplinary Head and Neck Center, National Institute of Oncology, Budapest, Hungary
3: Department of Thoracic Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
4: National Koranyi Institute of Pulmonology, Budapest, Hungary
5: Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
6: Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
7: Department of Biomedical Engineering, Lund University, Lund, Sweden
8: Department of Thoracic Surgery, Klinik Floridsdorf, Vienna, Austria
9: Center for Cancer Research, Medical University of Vienna, Vienna, Austria
10: Department of Translational Medicine, Lund University, Sweden
Bemutatás módja
Szóbeli
Szekció
Pathological and Oncological Sciences III.
Language of the presentation
English
Preferred session
Pathological and Oncological Sciences
Összefoglaló szövege
INTRODUCTION: Despite being one of the most aggressive tumors, there were no relevant breakthroughs in the therapeutic approach of small cell lung cancer (SCLC) for decades. BCL-2 family members are involved in apoptosis regulation and represent therapeutic targets in many malignancies.
AIMS: We aimed to investigate the subtype-specific expression pattern of the BCL-2 family members and to analyze the effectiveness of BCL-2/MCL-1 dual inhibition in human SCLC.
METHODS: We performed qPCR, Western blot, and MS-based proteomics on 27 SCLC cell lines. The effectiveness of the BCL-2 and MCL-1 inhibitors (venetoclax and S63845) was examined by using MTT-assay, flow cytometry and in vivo mouse models. Ectopic BAX overexpression was achieved by expression plasmids. Drug interactions were calculated using the Combenefit software. To confirm our preclinical findings, BCL-2 expression was measured on surgically removed human tissue samples.
RESULTS: The highest BCL-2 expression was observed in the SCLC-A and -P subtypes. Although sensitivity to venetoclax was reflected by BCL-2 levels, not all cell lines responded consistently despite their high BCL-2 expression. Venetoclax resistant cell lines had an elevated level of MCL-1 and a lower expression of BAX. In contrast, other members of the BCL-2 family had no effect on therapeutic response. A combination of venetoclax and S63845 resulted in a significant, synergistic in vitro and in vivo anti-tumor activity and apoptosis induction in double-resistant cells. In non-responding cells, BAX overexpression sensitized them to venetoclax and S63845 and induced synergistic drug interaction.
CONCLUSIONS: Here we provide evidence that dual targeting of BCL-2 and MCL-1 in the presence of BAX breaks venetoclax resistance in human SCLC and offers novel therapeutic approaches.
FUNDING: VP: New National Excellence Program of the Hungarian Ministry for Innovation and Technology (UNKP‐23‐3).
BD and ZM : Hungarian National Research, Development, and Innovation Office (2020‐1.1.6‐JÖVŐ, TKP2021‐EGA‐33, FK‐143751, FK-147045).
ZM: New National Excellence Program of the Ministry for Innovation and Technology of Hungary (UNKP‐20‐3, UNKP‐21‐3, UNKP-23-5), Bolyai Research Scholarship of the Hungarian Academy of Sciences, International Association for the Study of Lung Cancer/International Lung Cancer Foundation Young Investigator Grant (2022).
University
Semmelweis University
Supervisor
Dr. Megyesfalvi Zsolt Ph.D.
Publication of my abstract
I do not give consent to the publication of my abstract on the website of the congress.
Kind
Szabad
Status
elfogadva
Accepted presentation method
szóbeli
Előadás fájl jóváhagyás
nem rendelkezett róla
Előadó
8065
Start
10:30
End
10:40