Examining the In-Vitro Efficacy of the IAP Antagonist Birinapant as a Single-Agent or in Combination with Dacarbazine to Induce Melanoma Cell Death
Authors: Vetma, Vesna 1, 2, 3; Rožanc, Jan 4; Charles, Emilie M 1, 2; Hellwig, Christian T 1, 2, 3, 5; Alexopoulos, Leonidas G 4, 6; Rehm, Markus 1, 2, 3, 5
Affiliations: 1: Department of Physiology & Medical Physics 2: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland 3: Institute of Cell Biology and Immunology, University of Stuttgart, Germany 4: ProtATonce Ltd, Science Park Demokritos, Athens, Greece 5: Stuttgart Research Center Systems Biology, University of Stuttgart, Germany 6: Department of Mechanical Engineering, National Technical University of Athens, Greece
Abstract
Antagonists of inhibitor of apoptosis proteins (IAPs), alone or in combination with genotoxic therapeutics, have been shown to efficiently induce cell death in various solid tumours. The IAP antagonist birinapant is currently being tested in phase II clinical trials. We herein aimed to investigate the in vitro anti-tumour efficacy of dacarbazine, both as a single agent and in combination with birinapant, in melanoma cell lines. Covering clinically relevant drug concentration ranges, we conducted a total of 5400 measurements in a panel of 12 human melanoma cell lines representing different stages of disease progression. Surprisingly, functionally relevant synergies or response potentiation in combination treatments were not observed, and only one cell line modestly responded to birinapant single-treatment (approximately 16% cell death). While we did not study the underlying resistance mechanisms or more complex in vivo scenarios in which dacarbazine/birinapant response synergies may possibly still manifest, our findings are nevertheless noteworthy, since IAP antagonists were demonstrated to strongly enhance responses to DNA-damaging agents in cell lines of other cancer types under comparable experimental conditions in vitro.