Crizotinib – Molekulare Therapie des Lungenkarzinoms

Zusammenfassung

Die anaplastische Lymphomkinase (ALK) kann durch eine Gen-Translokation überaktiviert werden und dadurch ein Schlüsselonkogen bei der Progression von Tumorzellen werden. Bei ungefähr 5 % aller Patienten mit fortgeschrittenem nicht-kleinzelligem Lungenkarzinom (NSCLC) lässt sich mittels FISH (Fluoreszenz-in-situ-Hybridisierung) ein Fusionsgen, bestehend aus EML4 (echinoderm microtubule-associated protein-like 4) und ALK, nachweisen, welches zu einer Überaktivierung von ALK führt. Weitere Labortechniken können eine veränderte ALK-Expression nachweisen, wobei die Vergleichbarkeit mit FISH-Ergebnissen unterschiedlich ist. Crizotinib ist eine kleinmolekulare Substanz, die die ALK-Tyrosinkinaseaktivität hemmt. Die Behandlung mit Crizotinib von vorbehandelten NSCLC-Patienten, bei denen EML4-ALK-Fusionsgene nachgewiesen wurden, zeigte in klinischen Studien ein verbessertes Ansprechen und verlängertes progressionsfreies Überleben (PFS) im Vergleich zur Standard-Chemotherapie. Im Folgenden sollen Nachweismethoden und klinische Daten dargestellt werden.

Abstract

The anaplastic lymphoma kinase (ALK) can act as a key oncogenic driver after activation by means of processes such as gene rearrangement. In approximately 5 % of patients with advanced non-small cell lung cancer (NSCLC), an oncogenic fusion gene of echinoderm microtubule-associated protein-like 4 (EML4) and ALK has been detected using fluorescence in situ hybridisation (FISH). Moreover, various methods including immunohistochemistry and PCR-based assays can be used for analysing ALK expression. Clinical data have been generated for crizotinib, a small molecule inhibitor of the ALK receptor tyrosine kinase, demonstrating a substantial improvement of objective response rate and prolonged progression-free survival (PFS) compared to standard chemotherapy in pretreated NSCLC patients harbouring EML4-ALK fusion genes. In the current review, recent data on the detection and inhibition of ALK in advanced NSCLC are summarised.

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