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Ref Type Journal Article
PMID (26554404)
Authors Infarinato NR, Park JH, Krytska K, Ryles HT, Sano R, Szigety KM, Li Y, Zou HY, Lee NV, Smeal T, Lemmon MA, Mossé YP
Title The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma.
Journal Cancer discovery
Vol 6
Issue 1
Date 2016 Jan
URL
Abstract Text Neuroblastomas harboring activating point mutations in anaplastic lymphoma kinase (ALK) are differentially sensitive to the ALK inhibitor crizotinib, with certain mutations conferring intrinsic crizotinib resistance. To overcome this clinical obstacle, our goal was to identify inhibitors with improved potency that can target intractable ALK variants such as F1174L. We find that PF-06463922 has high potency across ALK variants and inhibits ALK more effectively than crizotinib in vitro. Most importantly, PF-06463922 induces complete tumor regression in both crizotinib-resistant and crizotinib-sensitive xenograft mouse models of neuroblastoma, as well as in patient-derived xenografts harboring the crizotinib-resistant F1174L or F1245C mutations. These studies demonstrate that PF-06463922 has the potential to overcome crizotinib resistance and exerts unprecedented activity as a single targeted agent against F1174L and F1245C ALK-mutated xenograft tumors, while also inducing responses in an R1275Q xenograft model. Taken together, these results provide the rationale to move PF-06463922 into clinical trials for treatment of patients with ALK-mutated neuroblastoma.The next-generation ALK/ROS1 inhibitor PF-06463922 exerts unparalleled activity in ALK-driven neuroblastoma models with primary crizotinib resistance. Our biochemical and in vivo data provide the preclinical rationale for fast-tracking the development of this agent in children with relapsed/refractory ALK-mutant neuroblastoma.

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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 R1275Q neuroblastoma conflicting Crizotinib Preclinical - Cell line xenograft Actionable In a preclinical study, Xalkori (crizotinib) did not inhibit growth of neuroblastoma cells over expressing ALK R1275Q in culture, and only delayed tumor growth in cell line xenograft models (PMID: 26554404). 26554404
EML4 - ALK neuroblastoma sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited growth of neuroblastoma cells harboring EML4-ALK in culture (PMID: 26554404). 26554404
ALK F1245C neuroblastoma sensitive Lorlatinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited growth of neuroblastoma cells over expressing ALK F1245C in culture, and induced rapid and sustained complete tumor regression in patient-derived xenograft models harboring ALK F1245C (PMID: 26554404). 26554404
ALK R1275Q neuroblastoma sensitive Lorlatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lorbrena (lorlatinib) inhibited Alk phosphorylation, resulted in growth inhibition of neuroblastoma cells over expressing ALK R1275Q in culture and irapid and sustained complete tumor regression in cell line xenograft models (PMID: 26554404). 26554404
ALK F1174L neuroblastoma resistant Crizotinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Xalkori (crizotinib) did not inhibit growth of neuroblastoma cells over expressing ALK F1174L in culture, and only delayed tumor growth in patient-derived and cell line xenograft models harboring ALK F1174L (PMID: 26554404). 26554404
ALK F1245C Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited foci formation more efficiently than Xalkori (crizotinib) in transformed cells over expressing ALK F1245C in culture (PMID: 26554404). 26554404
EML4 - ALK neuroblastoma resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) did not inhibit growth of neuroblastoma cells over expressing EML4-ALK in culture (PMID: 26554404). 26554404
ALK amp neuroblastoma sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited growth of ALK amplified neuroblastoma cells in culture (PMID: 26554404). 26554404
ALK wild-type neuroblastoma resistant Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) did not inhibit growth of ALK wild-type neuroblastoma cells in culture (PMID: 26554404). 26554404
ALK F1174L Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited foci formation more efficiently than Xalkori (crizotinib) in transformed cells over expressing ALK F1174L in culture (PMID: 26554404). 26554404
ALK R1275Q Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorlatinib (PF-06463922) inhibited foci formation more efficiently than Xalkori (crizotinib) in transformed cells over expressing ALK R1275Q in culture (PMID: 26554404). 26554404
ALK F1245C neuroblastoma resistant Crizotinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Xalkori (crizotinib) did not inhibit growth of neuroblastoma cells over expressing ALK F1245C in culture, and only delayed tumor growth in patient-derived xenograft models harboring ALK F1245C (PMID: 26554404). 26554404
ALK amp neuroblastoma sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) was less efficient than Lorlatinib (PF-06463922) to induced growth inhibition in ALK-amplified neuroblastoma cells in culture (PMID: 26554404). 26554404
ALK F1174L neuroblastoma conflicting Lorlatinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) inhibited growth of neuroblastoma cells over expressing ALK F1174L in culture, and induced rapid and sustained complete tumor regression in both patient-derived and cell line xenograft models harboring ALK F1174L (PMID: 26554404). 26554404