Kinome Reprogramming of G2/M Kinases and Repression of MYCN Contribute to Superior Efficacy of Lorlatinib in ALK-Driven Neuroblastoma.
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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 chemical proteomics approach to quantitatively measure functional kinome dynamics in response to lorlatinib and crizotinib in clinically relevant ALK-driven neuroblastoma patient-derived xenograft models. Lorlatinib was a markedly more potent inhibitor of ALK and preferentially downregulated several kinases implicated in G2/M cell-cycle transition compared with crizotinib. Lorlatinib treatment also led to the repression of MYCN expression and its occupancy at promoters of the same G2/M kinases. These data provide mechanistic insight into the superior efficacy of lorlatinib over crizotinib for the treatment of ALK-driven neuroblastoma.