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Lorlatinib, a third generation ALK/ROS inhibitor, overcomes de novo resistance and induces complete tumor regressions in patient-derived xenograft (PDX) 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 the ALK inhibitors lorlatinib and crizotinib, in clinically relevant ALK-driven neuroblastoma PDX models. Lorlatinib was a markedly more potent inhibitor of ALK and preferentially downregulated several kinases implicated in G2/M cell cycle transition compared to crizotinib. Lorlatinib treatment also led to the repression of MYCN expression and its occupancy at promoters of the same G2/M kinases. These data providing mechanistic insight in neuroblastoma into the far improved efficacy of lorlatinib over crizotinib for the treatment of ALK-driven neuroblastoma. Overall design: To investigate transcriptomic changes upon treatment with ALK inhibitors in neuroblastoma models, we treated mice bearing NB1643 cell derived xenograft (CDX) or COG-N-453 patient derived xenograft (PDX) with vehicle, crizotinib or lorlatinib for 2 days. We performed comparative gene expression analysis on the RNA seq data obtained from the two models.ENAALK, Neuroblastoma (Schwannian Stroma-Poor), NBLST3, Memory, neuroblastoma, DAlk53, False, Nmyc, 7-amino-12-fluoro-2, PF-06463922, Central neuroblastoma, ODED, mycna, mycnb, 16-trimethyl-15-oxo-10, PF06463922, Phosphotransferases, Sympathicoblastoma, Memories, 10, DAlk, mycn, 15, 16, Repressed, 3-H)(2, False Memory Syndrome, 4-(metheno)pyrazolo(4, mili, (10R)-7-amino-12-fluoro-2, Repressed Memory, NMYC, c-nmyc, CG8250, 11)benzoxadiazacyclotetradecine-3-carbonitrile, Tcrz, dALK, NOS, NB, Kinase, 5, nmyc, Phosphotransferase, xN-myc1, Transphosphorylases, Delayed Memories, Neuroblastomas, Repression, Neuroblastoma, Kinases, 3-h)(2, Nmyc1, Transphosphorylase, N-myc, Nmuc1, Memory Syndrome, False Memory Syndromes, neuroblastoma (morphologic abnormality), Nmyc-1, [M]Neuroblastoma NOS (morphologic abnormality), loratinib, Delayed, MODED, False Memory, Psychology Repression, (Neuroblastoma NOS) or (sympathicoblastoma), XN-myc, 17-tetrahydro-2H-8, [M]Neuroblastoma NOS, neuroblastoma NOS (morphologic abnormality)., Syndrome, Delayed Memory, NB - Neuroblastoma, Lorbrena, bHLHe37, ATP Phosphotransferases, XNmyc, CD246, ATP, DmelCG8250ALK, Neuroblastoma (Schwannian Stroma-Poor), NBLST3, Memory, neuroblastoma, DAlk53, False, Nmyc, 7-amino-12-fluoro-2, PF-06463922, Central neuroblastoma, ODED, mycna, mycnb, 16-trimethyl-15-oxo-10, PF06463922, Phosphotransferases, Sympathicoblastoma, Memories, 10, DAlk, mycn, 15, 16, Repressed, 3-H)(2, False Memory Syndrome, 4-(metheno)pyrazolo(4, mili, (10R)-7-amino-12-fluoro-2, Repressed Memory, NMYC, c-nmyc, CG8250, 11)benzoxadiazacyclotetradecine-3-carbonitrile, Tcrz, dALK, NOS, NB, Kinase, 5, nmyc, Phosphotransferase, xN-myc1, Transphosphorylases, Delayed Memories, Neuroblastomas, Repression, Neuroblastoma, Kinases, 3-h)(2, Nmyc1, Transphosphorylase, N-myc, Nmuc1, Memory Syndrome, False Memory Syndromes, neuroblastoma (morphologic abnormality), Nmyc-1, [M]Neuroblastoma NOS (morphologic abnormality), loratinib, Delayed, MODED, False Memory, Psychology Repression, (Neuroblastoma NOS) or (sympathicoblastoma), XN-myc, 17-tetrahydro-2H-8, [M]Neuroblastoma NOS, neuroblastoma NOS (morphologic abnormality)., Syndrome, Delayed Memory, NB - Neuroblastoma, Lorbrena, bHLHe37, ATP Phosphotransferases, XNmyc, CD246, ATP, DmelCG8250falseKinome reprogramming of G2/M kinases and repression of MYCN contribute to superior efficacy of lorlatinib in ALK-driven neuroblastomaKinome reprogramming of G2/M kinases and repression of MYCN contribute to superior efficacy of lorlatinib in ALK-driven neuroblastoma2025-09-242024-07-31PRJNA1141470GSE273349960639907037