Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers
Open Access
- 17 September 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 29 (3), 492-503
- https://doi.org/10.1038/s41418-021-00869-x
Abstract
Primary or acquired therapy resistance is a major obstacle to the effective treatment of cancer. Resistance to apoptosis has long been thought to contribute to therapy resistance. We show here that recombinant TRAIL and CDK9 inhibition cooperate in killing cells derived from a broad range of cancers, importantly without inducing detectable adverse events. Remarkably, the combination of TRAIL with CDK9 inhibition was also highly effective on cancers resistant to both, standard-of-care chemotherapy and various targeted therapeutic approaches. Dynamic BH3 profiling revealed that, mechanistically, combining TRAIL with CDK9 inhibition induced a drastic increase in the mitochondrial priming of cancer cells. Intriguingly, this increase occurred irrespective of whether the cancer cells were sensitive or resistant to chemo- or targeted therapy. We conclude that this pro-apoptotic combination therapy has the potential to serve as a highly effective new treatment option for a variety of different cancers. Notably, this includes cancers that are resistant to currently available treatment modalities.Funding Information
- Wellcome Trust (214342/z/18/z)
- Deutsche Forschungsgemeinschaft (SFB1399, C06, SFB1403-414786233, 432038712, SFB1399, A05, SFB1403, A05)
- Alexander von Humboldt-Stiftung
- Deutsche Krebshilfe (701125509)
This publication has 57 references indexed in Scilit:
- Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axisThe EMBO Journal, 2013
- Cyclin-dependent kinase inhibitors move into Phase IIINature Reviews Drug Discovery, 2012
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and BortezomibBritish Journal of Cancer, 2010
- Preclinical Differentiation between Apparently Safe and Potentially Hepatotoxic Applications of TRAIL Either Alone or in Combination with Chemotherapeutic DrugsClinical Cancer Research, 2006
- Molecular mechanisms of drug resistanceThe Journal of Pathology, 2005
- Safety and antitumor activity of recombinant soluble Apo2 ligandJCI Insight, 1999
- Induction of Apoptosis by Apo-2 Ligand, a New Member of the Tumor Necrosis Factor Cytokine FamilyOnline Journal of Public Health Informatics, 1996
- Identification and characterization of a new member of the TNF family that induces apoptosisImmunity, 1995
- Lethal effect of the anti-Fas antibody in miceNature, 1993