Montinaro, Antonella, Areso Zubiaur, Itziar, Saggau, Julia, Kretz, Anna-Laura, Ferreira, Rute M. M., Hassan, Omar, Kitzig, Ella, Mueller, Ines, El-Bahrawy, Mona A., von Karstedt, Silvia, Kulms, Dagmar, Liccardi, Gianmaria, Lemke, Johannes and Walczak, Henning (2022). Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers. Cell Death Differ., 29 (3). S. 492 - 504. LONDON: SPRINGERNATURE. ISSN 1476-5403

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Montinaro, AntonellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Areso Zubiaur, ItziarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saggau, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kretz, Anna-LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferreira, Rute M. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hassan, OmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kitzig, EllaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, InesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
El-Bahrawy, Mona A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Karstedt, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kulms, DagmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liccardi, GianmariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lemke, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walczak, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-594389
DOI: 10.1038/s41418-021-00869-x
Journal or Publication Title: Cell Death Differ.
Volume: 29
Number: 3
Page Range: S. 492 - 504
Date: 2022
Publisher: SPRINGERNATURE
Place of Publication: LONDON
ISSN: 1476-5403
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL-DEATH; TRAIL; LIGAND; RESISTANCE; CDK9; DIFFERENTIATION; MECHANISMS; INHIBITORS; RECEPTOR; BIOLOGYMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59438

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