The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma

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