Immunoassays for the quantification of ALK and phosphorylated ALK support the evaluation of on‐target ALK inhibitors in neuroblastoma. Issue 8 (31st May 2017)

• Record Type: Journal Article
• Authors: Tucker, Elizabeth R.; Tall, Jennifer R.; Danielson, Laura S.; Gowan, Sharon; Jamin, Yann; Robinson, Simon P.; Banerji, Udai; Chesler, Louis
• Is Part Of: Molecular oncology. Volume 11:Issue 8(2017)
• Page Start: 996
• Page End: 1006
• Publication Date: 2017-05-31
• Subjects: ALK -- neuroblastoma; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12069
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Targeted inhibition of anaplastic lymphoma kinase (ALK) is a successful approach for the treatment of many ALK‐aberrant malignancies; however, the presence of resistant mutations necessitates both the development of more potent compounds and pharmacodynamic methods with which to determine their efficacy. We describe immunoassays designed to quantitate phosphorylation of ALK, and their use in preclinical models of neuroblastoma, a pediatric malignancy in which gain‐of‐function ALK mutations predict a poor overall outcome to conventional treatment. Validation of the immunoassays is presented using a panel of neuroblastoma cell lines and evidence of on‐target ALK inhibition provided by treatment of a genetically engineered murine model of neuroblastoma with two clinical ALK inhibitors, crizotinib and ceritinib, highlighting the superior efficacy of ceritinib. Abstract : Targeted therapeutics against anaplastic lymphoma kinase (ALK) are being used to treat patients with ALK‐aberrant cancers but resistant mutations require more potent compounds and methods with which to screen their efficacy. We have developed immunoassays to quantify expression of ALK and its phosphorylated forms, then tested their use in preclinical models of neuroblastoma using two clinical inhibitors, crizotinib and ceritinib.