{"doi":"10.17615/pbz0-mn14","title":"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/ROS inhibitor, overcomes de novo resistance and induces complete and sustained 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 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 into the superior efficacy of lorlatinib over crizotinib for the treatment of ALK-driven neuroblastoma.","journal":"UNC Libraries","year":2025,"id":577306,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1394154,"name":"Mark Gerelus","orcid":"0000-0001-8986-4523","position":1,"is_corresponding":false},{"id":373284,"name":"Michael P. East","orcid":"0000-0002-1994-6117","position":2,"is_corresponding":false},{"id":289102,"name":"Alvin Farrel","orcid":"0000-0003-1087-9840","position":3,"is_corresponding":false},{"id":478897,"name":"Steven Pastor","orcid":"0000-0002-4204-1383","position":4,"is_corresponding":false},{"id":240511,"name":"John M. Maris","orcid":"0000-0002-8088-7929","position":5,"is_corresponding":false},{"id":1394153,"name":"Colleen E. Casey","orcid":"0009-0004-9259-1035","position":6,"is_corresponding":false},{"id":564616,"name":"Yaël P. Mossé","orcid":"0000-0002-3463-0399","position":7,"is_corresponding":false},{"id":808566,"name":"Kateryna Krytska","orcid":null,"position":8,"is_corresponding":false},{"id":2220,"name":"Gary L. Johnson","orcid":"0000-0003-2867-0551","position":9,"is_corresponding":false},{"id":1003684,"name":"Esther R. Berko","orcid":"0000-0001-7181-1378","position":10,"is_corresponding":false},{"id":1394151,"name":"Gabriela M. Witek","orcid":"0000-0003-2635-773X","position":11,"is_corresponding":false},{"id":550692,"name":"Khushbu Patel","orcid":"0000-0002-3269-7442","position":12,"is_corresponding":false},{"id":1394150,"name":"Smita Matkar","orcid":"0000-0002-5697-2576","position":13,"is_corresponding":false},{"id":533123,"name":"Timothy J. Stuhlmiller","orcid":"0009-0005-0946-2257","position":14,"is_corresponding":false},{"id":1394807,"name":"Joshua R. Kalna","orcid":null,"position":15,"is_corresponding":false},{"id":1176544,"name":"Denis O. Okumu","orcid":"0000-0002-4791-0453","position":16,"is_corresponding":false},{"id":1394152,"name":"Anne Kennedy","orcid":"0000-0003-2701-2637","position":17,"is_corresponding":false},{"id":29525,"name":"Hakon Hakonarson","orcid":"0000-0003-2171-3627","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:58:04.622308Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}