Kinome Reprogramming of G2/M Kinases and Repression of MYCN Contribute to Superior Efficacy of Lorlatinib in ALK-Driven Neuroblastoma.

ABSTRACT: Mutations in the tyrosine kinase domain of the anaplastic lymphoma kinase (ALK) oncogene in neuroblastoma occur most frequently at one of three hotspot amino acid residues, with the F1174* and F1245* variants conferring de novo resistance to first- and second-generation ALK inhibitors, including crizotinib and ceritinib. Lorlatinib, a third-generation ALK/ROS1 inhibitor, overcomes de novo resistance and induces complete and sustained tumor regressions in patient-derived xenograft models unresponsive to crizotinib. Lorlatinib has now completed phase 1 testing in children and adults with relapsed/refractory ALK-driven neuroblastoma and entered pivotal phase 3 testing within the Children's Oncology Group. To define mechanisms underlying the superior activity of lorlatinib, we utilized a chemi

SUBMITTER: Matkar S 

PROVIDER: S-EPMC12322148 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature