Membranrezeptorsignale und Kontrolle der DNA-Reparatur nach ionisierender Strahlung

Zusammenfassung

Zahlreiche präklinische und klinische Ergebnisse belegen, dass die Aktivität von erbBRezeptoren, die in Zellen solider Tumore einerseits durch Mutation oder durch Genamplifikation und somit Überexpression der Rezeptoren gegeben sein kann, sowohl für Chemoals Radiotherapie-Resistenz verantwortlich ist. In diesem Zusammenhang induzieren Signalkaskaden, die z. B. durch den epidermalen Wachstumsfaktor-Rezeptor EGFR (erbB1) im Falle seiner abnormalen Aktivität stimuliert werden, spezifische Zellüberlebensmechanismen, durch die eine Resistenz gegen ionisierende Strahlung verursacht wird. Verschiedene In-vitro- und In-vivo-Studien belegen, dass durch so genannte molekulare Targeting-Strategien, die gegen den EGFR gerichtet sind, die Radiotoxizität der Strahlentherapie verstärkt werden kann. Hierbei korreliert der radiosensitivierende Effekt von EGFR-Antagonisten primär mit einer Unterdrückung der Kapazität von Tumorzellen für die Reparatur strahleninduzierter DNA-Doppelstrangbrüche, die über den nicht homologen End-Joining-Reparaturmechanismus ablaufen.

In dieser Übersicht wird die Rolle und Bedeutung des EGFR und erbB2-Rezeptors in der Transduktion strahleninduzierte Signale über die PI3K-Akt-Kaskade und die Beeinflussung der DNA-Doppelstrangbruchreparatur durch diesen Signalweg besprochen und die radiosensitivierenden Effekte entsprechender Antagonisten diskutiert. Das zunehmende Verständnis des mechanistischen Prinzips, wie erbB-Rezeptor-Signalwege in die Regulation der DNADoppelstrangbruchreparatur eingreifen, wird translationelle Ansätze zur Überprüfung neuer Strategien für die klinische Anwendung des molekularen Targeting stimulieren.

Schlüsselwörter

EGFR - PI3K-Akt-Signaltransduktion - DNAReparatur - Strahlenreaktion

• References

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