Purpose: Neuroblastoma harbouring amplification of the MYCN oncogene is associated with high-risk disease and poor clinical outcome. While therapies targeting Anaplastic Lymphoma Kinase (ALK) have shown success in neuroblastoma with relevant mutations, patients with MYCN-amplified tumors lacking these mutations have limited treatment options. This study aimed to investigate whether inhibition of ALK impacted on the therapeutic potential of targeting replication stress in MYCN-driven neuroblastoma in the absence of activating ALK mutations. Experimental Design: We used a MYCN-driven genetically engineered mouse model of neuroblastoma. Genetic deletion of ALK was performed to assess its role in MYCN-driven tumor development. In addition, pharmacologic inhibition of ataxia telangiectasia and Rad3-related protein, alone or in combination with ALK inhibition, was tested in tumor bearing mice over a 14-day treatment period and 200 day follow-up period. Results: Genetic removal of ALK significantly reduced tumor penetrance in mice with MYCN-driven neuroblastoma. Treatment with the ataxia telangiectasia and Rad3-related protein inhibitor led to survival benefit, which was significantly enhanced when combined with anaplastic lymphoma kinase inhibition. Combination treatment resulted in durable tumor suppression and extended survival beyond that achieved with monotherapy. Conclusions: These findings highlight an important role for ALK in supporting tumor growth in MYCN-driven neuroblastoma without that lack ALK-activating mutations. Targeting replication stress in combination with ALK inhibition represents a promising therapeutic strategy for a high-risk patient population with limited targeted treatment options.
Borenäs et al. (Mon,) studied this question.