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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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