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Ref Type Journal Article
PMID (27483357)
Authors Guan J, Tucker ER, Wan H, Chand D, Danielson LS, Ruuth K, El Wakil A, Witek B, Jamin Y, Umapathy G, Robinson SP, Johnson TW, Smeal T, Martinsson T, Chesler L, Palmer RH, Hallberg B
Title The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.
Journal Vol Issue Date Pages Journal Short Title
Disease models & mechanisms 9 9 2016 Sep 01 941-52 Dis Model Mech
URL
Abstract Text The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALK(F1174L)/MYCN Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK Y1278S Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) treatment inhibited Alk phosphorylation and viability in transformed cells expressing ALK Y1278S in culture (PMID: 27483357). 27483357
ALK F1174L neuroblastoma predicted - sensitive Lorlatinib Preclinical Actionable In a preclinical study, Lorbrena (lorlatinib) treatment induced tumor regression in a transgenic mouse model of neuroblastoma harboring ALK F1174L (PMID: 27483357). 27483357
ALK F1174I Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) treatment inhibited Alk phosphorylation and viability in transformed cells expressing ALK F1174I in culture (PMID: 27483357). 27483357
ALK R1192P Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) treatment inhibited Alk phosphorylation and viability in transformed cells expressing ALK R1192P in culture (PMID: 27483357). 27483357
ALK F1174V neuroblastoma sensitive Lorlatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lorbrena (lorlatinib) treatment inhibited proliferation of a neuroblastoma cell line harboring ALK F1174V in culture and inhibited tumor growth in a cell line xenograft model (PMID: 27483357). 27483357
ALK F1174L Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) treatment inhibited Alk phosphorylation and viability in transformed cells expressing ALK F1174L in culture (PMID: 27483357). 27483357
ALK G1269A Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) treatment inhibited Alk phosphorylation and viability in transformed cells expressing ALK G1269A in culture (PMID: 27483357). 27483357
ALK del exon4-11 neuroblastoma sensitive Lorlatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lorbrena (lorlatinib) treatment inhibited proliferation of a neuroblastoma cell line harboring deletion of ALK exons 4-11 in culture and inhibited tumor growth in a cell line xenograft model (PMID: 27483357). 27483357
ALK F1245C Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) treatment inhibited Alk phosphorylation and viability in transformed cells expressing ALK F1245C in culture (PMID: 27483357). 27483357