Abstract 3109: ALK as a valid therapeutic target for the treatment of rhabdomyosarcoma

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor tyrosine kinase, a member of the insulin receptor family, with a tightly controlled expression pattern. Deregulated ALK expression has been linked to the development of several types of cancers. Typically, chromosomal translocations involving ALK generate constitutively expressed chimeric oncoproteins, such as NPM-ALK in anaplastic large cell lymphoma and EML4-ALK in non-small cell lung carcinoma. However, activating mutations in ALK, and increased copy number that result in aberrant gene expression, have also been observed in neuroblastoma and colorectal cancers. Based on the above observations, several small molecule ALK inhibitors have been developed and are in clinical trials for a variety of tumors expressing this kinase. This has resulted in the use of crizotinib for the treatment of EML4-ALK + lung cancers. Recently several large scale immunohistochemistry and genome sequencing studies of pediatric rhabdomyosarcoma (RMS) revealed aberrant ALK expression. It was found that ALK mRNA expression was significantly different in alveolar (ARMS) and embryonic RMS (ERMS), the two major histological subtypes in children. Thus, ALK expression might play a role in tumorigenesis for this disease, and this kinase may represent a valid therapeutic target for the treatment of RMS. To answer this question we analyzed ALK expression in a large panel of RMS cell lines, and pediatric tumor samples by quantitative PCR and immunoblotting. We also compared the sensitivity of these cells to a series of ALK inhibitors. Our results indicate that the majority of ARMS cell lines demonstrated significantly higher ALK mRNA expression as compared to ERMS, and to normal human myoblast control cells. This was confirmed by western analysis. Growth inhibition assays confirmed that all RMS lines were more sensitive to crizotinib and LDK-378 than control lines, consistent with the hypothesis that ALK is a driver of cell growth in these tumors. Based on our in vitro analysis, we suggest that ALK inhibition may represent an effective therapeutic modality for the treatment of ALK+ RMS. Preclinical studies to confirm or disprove this hypothesis are currently underway. Supported by St. Jude Children's Research Hospital and by the American Lebanese Syrian Associated Charities Citation Format: Monika Wierdl, Lyudmila Tsurkan, Viktor Tollemar, Lying Chi, Elizabeth Stewart, Michael A. Dyer, Philip M. Potter. ALK as a valid therapeutic target for the treatment of rhabdomyosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3109. doi:10.1158/1538-7445.AM2014-3109