(Vienna, 17-03-2023) Small cell lung cancer (SCLC) accounts for 15% of all lung cancer cases and remains one of the most lethal human cancer types. According to a recent multicenter study led by scientists from the MedUni Vienna, SCLC may be subclassified into specific molecular subtypes. New research from the same international team now suggests that a novel drug combination could be an effective option for patients with certain SCLC molecular profiles. The research findings have just been published in the British Journal of Cancer.
“Venetoclax is an oral drug that inhibits BCL2, a therapeutically targetable protein that prevents cancer cell death called apoptosis and is often overexpressed in SCLC. Venetoclax has been approved for the treatment of certain types of leukemias and is now being experimentally and clinically tested for SCLC as well”, says Zsolt Megyesfalvi (Department of Thoracic Surgery at the Medical University of Vienna), shared first author of the study.
Unfortunately, cancer cells often develop resistance to venetoclax, urging the need for more effective treatment strategies. In their new study study leader Balazs Döme (Department of Thoracic Surgery, Medical University of Vienna) and his team reported that venetoclax resistance of SCLC cells with elevated BCL2 levels is mainly due to the high expression of another anti-apoptotic protein called MCL-1.
In addition, the team’s research also showed that combining venetoclax with S63845, an MCL-1 inhibitor, is an effective approach to overcome venetoclax resistance in high BCL-2-expressing SCLCs. However, as study co-leader Karin Schelch added, “an intact pro-apoptotic protein called BAX is also required for this synergistic drug interaction”.
“These results are clinically important because they might open new avenues for strategic combinations to overcome treatment failures that have been identified with venetoclax monotherapy”, Balazs Döme notes. Notably, the study also demonstrated that venetoclax is an especially promising therapy in patients with specific SCLC molecular subtypes called SCLC-A and SCLC-P because the highest levels of BCL2 protein can be detected in these SCLC subgroups.
Publication: British Journal of Cancer
Dual targeting of BCL-2 and MCL-1 in the presence of BAX breaks venetoclax resistance in human small cell lung cancer
Zsuzsanna Valko, Zsolt Megyesfalvi, Anna Schwendenwein, Christian Lang, Sandor Paku, Nandor Barany, Bence Ferencz, Anita Horvath-Rozsas, Ildiko Kovacs, Erzsebet Schlegl, Veronika Pozonec, Kristiina Boettiger, Melinda Rezeli, Gyorgy Marko-Varga, Ferenc Renyi-Vamos, Mir Alireza Hoda, Thomas Klikovits, Konrad Hoetzenecker, Michael Grusch, Viktoria Laszlo, Balazs Dome, Karin Schelch