Emerging importance of ALK in neuroblastoma

Abstract

Since the original descriptions of gain-of function mutations in anaplastic lymphoma kinase (ALK), interest in the role of this receptor tyrosine kinase in neuroblastoma development and as a potential therapeutic target has escalated. As a group, the activating point mutations in full-length ALK, found in approximately 8% of all neuroblastoma tumors, are distributed evenly across different clinical stages. However, the most frequent somatic mutation, F1174L, is associated with amplification of the MYCN oncogene. This combination of features appears to confer a worse prognosis than MYCN amplification alone, suggesting a cooperative effect on neuroblastoma formation by these two proteins. Indeed, F1174L has shown more potent transforming activity in vivo than the second most common activating mutation, R1275Q, and is responsible for innate and acquired resistance to crizotinib, a clinically relevant ALK inhibitor that will soon be commercially available. These advances cast ALK as a bona fide oncoprotein in neuroblastoma and emphasize the need to understand ALK-mediated signaling in this tumor. This review addresses many of the current issues surrounding the role of ALK in normal development and neuroblastoma pathogenesis, and discusses the prospects for clinically effective targeted treatments based on ALK inhibition.

Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK–Positive Anaplastic Large Cell Lymphoma

“…4), extramedullary plasmacytoma (5), renal cell carcinoma (6), thyroid cancer (7), basal cell carcinoma (8), breast cancer, and colorectal cancer (9,10). Moreover, aberrant activation or overexpression of full-length ALK has an oncogenic role in neuroblastoma (11,12) and glioblastoma multiforme (13,14). The oncogenic properties of aberrantly activated ALK are mainly due to the deregulated activation of different downstream pathways such as RAS/ RAF/MEK/ERK1/2 and PCLg, involved in cellular proliferation, and PI3K/AKT and JAK3/STAT3, that promote cell survival (15)(16)(17).…”

Upregulation of MAPK Negative Feedback Regulators and RET in Mutant ALK Neuroblastoma: Implications for Targeted Treatment

“…Previous research work from our laboratory and others has identified activating mutations in the tyrosine kinase domain of the ALK transmembrane receptor tyrosine kinase, which are found in the majority of hereditary neuroblastoma and occur as somatic defects in 7% to 10% of sporadic cases (3)(4)(5)(6). During embryonic development, ALK is expressed in the central and peripheral nervous system (7), where it may regulate the interplay between cell proliferation and differentiation of the developing sympatho-adrenal cells of the neural crest (1, 8,9).…”

Advances in ALK Targeted Therapy for Neuroblastoma

“…It is an oral small-molecule tyrosine kinase inhibitor, originally developed as a c-MET inhibitor and later found an inhibitor for ALK phosphorylation [30,31]. In vitro studies demonstrated that crizotinib is potent in neuroblastoma cell lines with ALK amplification or the R1275Q mutation, one of the most common ALK variants in neuroblastoma [32]. Whereas cells bearing ALKF1174L mutation are relatively crizotinib-resistant [18,19,33,34].…”