Reference Detail

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 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 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 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
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 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 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 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 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 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