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DOI: 10.1055/s-0032-1313078
© Georg Thieme Verlag KG Stuttgart · New York
Synthetische Letalität als Therapiekonzept für die Behandlung maligner Neoplasien
Synthetic lethality as a new concept for the treatment of cancerPublication History
Publication Date:
23 August 2012 (online)
![](https://www.thieme-connect.de/media/tumor/201205/lookinside/thumbnails/10.1055-s-0032-1313078-1.jpg)
Zusammenfassung
Als Antwort auf DNA-Schäden aktivieren Zellen ein komplexes DNA-Schadensantwort-Signal-Netzwerk, um den Zellzyklus zu stoppen, DNA zu reparieren oder bei extensiven Schäden den apoptotischen Zelltod einzuleiten. Gene der DNA-Schadensantwort („DNA damage response“) sind unter den am häufigsten mutierten Genen in humanen Krebserkrankungen, und es wird angenommen, dass diese Läsionen einen „Mutator-Phänotyp“ hervorrufen, der die unkontrollierte Proliferation von Krebszellen fördert. Diese genetischen Läsionen können allerdings auch als die „Achilles-Ferse“ der Krebszellen betrachtet werden. Diese Vulnerabilitäten sind insbesondere aus klinischer Sicht hochinteressant, da sie genetisch-gesteuerte neue Therapieansätze für die Behandlung maligner Neoplasien liefern. Hier diskutieren wir ein solches personalisiertes Therapiekonzept – die synthetische Letalität. Wir erörtern die ersten erfolgreichen klinischen Anwendungen der synthetischen Letalität zur Therapie von Krebserkrankungen und beleuchten präklinische Entwicklungen, die vor dem Schritt in die klinische Testung stehen.
Abstract
Following DNA damage, cells activate a complex DNA-damage-response (DDR) signaling network to arrest the cell cycle, repair DNA and, if the extend of damage is beyond repair capacity, induce apoptosis. DDR genes are among the most commonly mutated genes in human cancer and it is believed that these lesions promote a „mutator-phenotype“ that fuels the runaway proliferation of cancer cells. However, these genetic lesions can also be seen as the „Achilles heel“ of cancer. These tumor cell-specific vulnerabilities are of extraordinary clinical interest, since they allow genetically-guided novel therapeutic regimens for the treatment of cancer. Here, we discuss such a novel therapeutic concept – synthetic lethality. We focus on the first successful clinical applications of synthetic lethality for the treatment of different cancer entities. In addition, we give a brief review of recently developed, synthetic lethality-based approaches that are close to clinical testing.
Schlüsselwörter
Krebs - Onkogen - Tumorsuppressorgen - synthetische Letalität
Keywords
cancer - oncogene - tumor suppressor gene - synthetic lethality
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Korrespondenzadresse
PD Dr. med. Hans Christian Reinhardt
Universitätsklinik Köln
Medizinische Klinik I
Weyertal 115B
50931 Köln
Phone: 0221/478-96701
Email: christian.reinhardt@uk-koeln.de