Mechanism of Crizotinib Resistance in Neuroblastoma Suggested

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(ChemotherapyAdvisor) – Development of new targeted therapies is needed for the treatment of ALK-positive neuroblastoma, according to a team of researchers of The Institute of Cancer Research, Sutton, Surrey, United Kingdom. This conclusion is a based on a study entitled “The ALK(F1174L) Mutation Potentiates the Oncogenic Activity of MYCN in Neuroblastoma,” which was published in Cancer Cell on July 10. 

The investigators premised the study on the following fact: “The ALK(F1174L) mutation is associated with intrinsic and acquired resistance to crizotinib and cosegregates with MYCN in neuroblastoma.” The aim of this preclinical study was to use a mouse model that overexpresses ALK(F1174L) in the neural crest to gain an understanding of its pathogenic role in neuroblastoma.

The investigators reported the following results. “Compared to ALK(F1174L) and MYCN alone, coexpression of these two oncogenes led to the development of neuroblastomas with earlier onset, higher penetrance, and enhanced lethality,” the investigators wrote. “ALK(F1174L)/ MYCN tumors exhibited increased MYCN dosage due to ALK(F1174L)-induced activation of the PI3K/AKT/mTOR and MAPK pathways, coupled with suppression of MYCN proapoptotic effects. Combined treatment with the ATP-competitive mTOR inhibitor Torin2 overcame the resistance of ALK(F1174L)/MYCN tumors to crizotinib.”

The investigators concluded: “These findings demonstrate a pathogenic role for ALK(F1174L) in neuroblastomas overexpressing MYCN and suggest a strategy for improving targeted therapy for ALK-positive neuroblastoma.”


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