The ALKF1174L Mutation Potentiates the Oncogenic Activity of MYCN in Neuroblastoma

SummaryThe ALKF1174L mutation is associated with intrinsic and acquired resistance to crizotinib and cosegregates with MYCN in neuroblastoma. In this study, we generated a mouse model overexpressing ALKF1174L in the neural crest. Compared to ALKF1174L and MYCN alone, co-expression of these two oncogenes led to the development of neuroblastomas with earlier onset, higher penetrance, and enhanced lethality. ALKF1174L/MYCN tumors exhibited increased MYCN dosage due to ALKF1174L-induced activation of the PI3K/AKT/mTOR and MAPK pathways, coupled with suppression of MYCN pro-apoptotic effects. Combined treatment with the ATP-competitive mTOR inhibitor Torin2 overcame the resistance of ALKF1174L/MYCN tumors to crizotinib. Our findings demonstrate a pathogenic role for ALKF1174L in neuroblastomas overexpressing MYCN and suggest a strategy for improving targeted therapy for ALK-positive neuroblastoma.

► A murine model of ALKF1174L/MYCN neuroblastoma is presented ► ALK potentiates MYCN-driven oncogenesis at multiple levels in neuroblastoma ► ALKF1174L/MYCN tumors exhibit therapy resistance in vivo ► mTOR inhibition circumvents crizotinib resistance in vivo