Anaplastic lymphoma kinase (ALK) is an important molecular target in 
neuroblastoma. Although tyrosine kinase inhibitors abrogating ALK activity are 
currently in clinical use for the treatment of ALK-positive (ALK(+)) disease, 
monotherapy with ALK tyrosine kinase inhibitors may not be an adequate solution 
for ALK(+) neuroblastoma patients. Increased expression of the gene encoding the 
transcription factor MYCN is common in neuroblastomas and correlates with poor 
prognosis. We found that the kinase ERK5 [also known as big mitogen-activated 
protein kinase (MAPK) 1 (BMK1)] is activated by ALK through a pathway mediated 
by phosphoinositide 3-kinase (PI3K), AKT, MAPK kinase kinase 3 (MEKK3), and MAPK 
kinase 5 (MEK5). ALK-induced transcription of MYCN and stimulation of cell 
proliferation required ERK5. Pharmacological or RNA interference-mediated 
inhibition of ERK5 suppressed the proliferation of neuroblastoma cells in 
culture and enhanced the antitumor efficacy of the ALK inhibitor crizotinib in 
both cells and xenograft models. Together, our results indicate that ERK5 
mediates ALK-induced transcription of MYCN and proliferation of neuroblastoma, 
suggesting that targeting both ERK5 and ALK may be beneficial in neuroblastoma 
patients.