Abstract
Abstract The purpose of this study was to identify therapeutically targetable mechanisms of resistance to anaplastic lymphoma kinase (ALK) inhibition in neuroblastoma. ALK is a receptor tyrosine kinase (RTK) frequently activated in neuroblastoma, a malignancy of the autonomic nervous system representing almost 10% of pediatric cancers. ALK aberrations, including mutation and amplification, lead to increased autophosphorylation and activation in neuroblastoma. PF-02341066, an orally available small-molecule inhibitor of the ALK tyrosine kinase, has shown dramatic activity in non-small lung cancers harboring an ALK translocation, and is currently in phase 1 trials in pediatrics. Although pharmacological inhibition of kinases in diseases such as chronic myelogenous leukemia has significantly improved survival, resistance inevitably develops. Mechanisms of resistance to tyrosine kinase inhibitors have included mutation of the targeted receptor as well as up-regulation and dependence switch to other RTKs. We hypothesize that patients with neuroblastoma who successfully respond to ALK inhibition will eventually relapse and that in vitro models can be used to predict the underlying mechanisms of resistance. To mimic the development of resistance, we treated ALK-expressing human neuroblastoma-derived cell lines in vitro with PF-02341066 for several months. Once resistance was established, serial dilutions were used to generate clonal populations of PF-02341066-resistant cells. Western blotting was used to confirm inhibition of phospho-ALK and rule out drug efflux as a resistance mechanism. DNA analysis revealed no additional PF-02341066-induced mutations or copy number variations within ALK. We next used Western blot and phoshpho-array technology to evaluate changes in the activation state of a panel of RTKs as well as their downstream signaling molecules. Interestingly, in comparison to the untreated parental line, PF-02341066-resistant cells had up-regulated activated epidermal growth factor receptor (EGFR) as well as other downstream signaling molecules. Dependence of the PF-02341066-resistant cells on these pathways was verified by showing increased sensitivity of the resistant versus parental cell lines to inhibition of these up-regulated pathways. Taken together, these data suggest that ALK inhibition in neuroblastoma leads to a dependence switch to EGFR and implies the need to develop therapeutic strategies to target this receptor when ALK inhibition is used clinically. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 742. doi:10.1158/1538-7445.AM2011-742
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