- Medicine & Science
Small cell lung cancer (SCLC) accounts for 15% of all lung cancer cases and is still associated with a particularly high mortality rate. According to a recent multicenter study led by MedUni Vienna, SCLC can be classified into specific molecular subtypes. New research from the same international team now suggests that a novel combination drug therapy could be an effective option for patients with specific molecular backgrounds. The research has just been published in the British Journal of Cancer.
"Venetoclax is an orally administered drug which belongs to the class of BCL2 inhibitors. This involves the inhibition of a protein involved in programmed cell death (apoptosis). BCL2 has been shown to be dysregulated in SCLC patients, making it an attractive target for personalized therapy. Venetoclax is already approved for the treatment of certain types of leukemia and is now also being tested experimentally and clinically for SCLC," says Zsolt Megyesfalvi (University Department of Thoracic Surgery, MedUni Vienna), one of the study’s first authors.
Cancer cells often develop resistance to venetoclax, highlighting the need for more effective treatment strategies. In their new study, lead investigator Balazs Döme of the University Department of Thoracic Surgery at the Medical University of Vienna and his team showed that venetoclax resistance in SCLC cells with elevated BCL2 expressions was mainly due to the high presence of another anti-apoptotic protein called MCL-1.
In addition, the team’s research revealed that combining venetoclax with S63845, an MCL-1 inhibitor, is an effective approach in venetoclax-resistant SCLCs with high BCL-2 expression. As study co-leader Karin Schelch (University Department of Thoracic Surgery, MedUni Vienna) added, -Yet, an intact pro-apoptotic protein called BAX is also required for this synergistic drug interaction."
-These results are clinically important as they open up new avenues for strategic combinations when venetoclax monotherapy fails," said Balazs Döme. The study also shows that venetoclax is a particularly promising approach for patients with certain molecular subtypes of SCLC, referred to as SCLC-A and SCLC-P. The basis for personalized therapy of these two SCLC subtypes is that increased expression of BCL2 protein can be detected. The basis for a personalized therapy option for these two SCLC subgroups is that increased expression of the BCL2 protein can be detected.
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.
DOI: https://doi.org/10.1038/s41416’023 -02219-9