Erk5 Is a Potential Therapeutic Target in Alk-positive Neuroblastoma

Anaplastic lymphoma kinase (ALK) has been implicated as an oncogenic driver in pediatric neuroblastoma and is frequently activated by amplifi cation and gain-of-function mutations. However, results from phase I trials have suggested that, in contrast to other tumor types such as non–small cell lung cancer, single-agent therapy with the ALK inhibitor crizotinib is not effective in pediatric patients with ALK-positive neuroblastoma, underscoring the need to identify additional therapeutic targets. Umapathy and colleagues found that ALK stimulated phosphorylation of the kinase ERK5 (also known as MAPK7) in ALK-positive neuroblastoma cell lines and that ERK5 activation was necessary for ALK-induced transcription of the oncogene MYCN, which is commonly amplifi ed in neuroblastoma and is associated with poor prognosis. ALK-driven activation of ERK5 was mediated by PI3K–AKT signaling and downstream phosphorylation of the ERK5 activator MEKK3 (also known as MAP3K3), and treatment with crizotinib or PI3K pathway inhibitors diminished the levels of phosphorylated ERK5 in the nucleus and reduced NMYC expression in neuroblastoma cells. Single-agent treatment with the ERK5 inhibitor XMD892 impaired the proliferation of ALK-positive, MYCN-amplifi ed neuroblastoma cell lines in vitro, indicating that ERK5 may be a potential therapeutic target. Furthermore, combined treatment with crizotinib and XMD8-92 synergistically decreased neuroblastoma cell growth, suggesting that ERK5 blockade may enhance the effi cacy of crizotinib in ALK-positive neuroblastoma. Consistent with this idea, dual inhibition of ALK and ERK5 more effectively inhibited the growth of ALK-positive xenograft tumors in vivo compared with single-agent treatment and resulted in reduced expression of NMYC in tumors. These fi ndings suggest that concomitant ALK and ERK5 inhibition may represent an effective therapeutic strategy to suppress oncogenic MYCN expression and potentially overcome crizotinib resistance in patients with ALK-positive neuroblastoma. ■