Abstract 5248: Neuroblastoma tumors with different ALK mutations are sensitive to Perifosine

Abstract

Abstract Background: Neuroblastoma (NB) is the most common extracranial solid tumor of children. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase predominantly expressed in the developing nervous system. Recently, mutated ALK has been identified in association with familial and sporadic neuroblastoma (NB). Patients whose tumors contain amplification, mutation or express increased levels of activated ALK have a poor prognosis. Downstream targets of ALK include the STAT and Akt pathways. Perifoisine is an Akt inhibitor that has been reported to inhibit tumor growth in adult pre-clinical models. The aim of this study was to assess whether ALK mutations affect the response of NB cells to perifosine. Methods: We selected 4 NB cell lines with different ALK mutation status (SY5Y-ALK F1174L mutation; KCNR-ALK R1275Q mutation, AS and NGP with wild-type (wt) ALK. The effect of perifosine on Akt phosphorylation and cell survival was evaluated in these cell lines. In vivo studies were also performed in nude mice by subcutaneous injection of NB cells with or without ALK mutation. The tumor growth and phosphorylated Akt levels in tumor tissues were studied. Results: In vitro, treatment with perifosine induced decreases in Akt phosphorylation in all the 4 cell lines. SY5Y-ALK F1174L which is reported to be sensitive to ALK inhibitor TAE684, and KCNR-ALK R1275Q, AS-ALK wt and NGP-ALK wt which are reported to be resistant to ALK inhibitor TAE684, all responded to perifosine treatment. In vivo, perifosine treatment delayed or inhibited growth of tumors containing mutant or wild-type ALK. The phosphorylated Akt levels were lower in tumors treated with perifosine compared to tumors treated with control reagent. Conclusions: These data indicate that Perifosine is able to control NB tumor cell growth despite the mutational status of ALK. Perifosine may be a candidate treatment for NB tumors not only for those with wt ALK but especially for those that carry mutations that are resistant to ALK inhibitor treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5248.