dc.contributor.author | Guan, J | |
dc.contributor.author | Tucker, ER | |
dc.contributor.author | Wan, H | |
dc.contributor.author | Chand, D | |
dc.contributor.author | Danielson, LS | |
dc.contributor.author | Ruuth, K | |
dc.contributor.author | El Wakil, A | |
dc.contributor.author | Witek, B | |
dc.contributor.author | Jamin, Y | |
dc.contributor.author | Umapathy, G | |
dc.contributor.author | Robinson, SP | |
dc.contributor.author | Johnson, TW | |
dc.contributor.author | Smeal, T | |
dc.contributor.author | Martinsson, T | |
dc.contributor.author | Chesler, L | |
dc.contributor.author | Palmer, RH | |
dc.contributor.author | Hallberg, B | |
dc.date.accessioned | 2016-12-07T14:28:07Z | |
dc.date.issued | 2016-09-01 | |
dc.identifier.citation | Disease models & mechanisms, 2016, 9 (9), pp. 941 - 952 | |
dc.identifier.issn | 1754-8403 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/315 | |
dc.identifier.eissn | 1754-8411 | |
dc.identifier.doi | 10.1242/dmm.024448 | |
dc.description.abstract | 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 941 - 952 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | COMPANY BIOLOGISTS LTD | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | PC12 Cells | |
dc.subject | Animals | |
dc.subject | Mice, Inbred BALB C | |
dc.subject | Mice, Nude | |
dc.subject | Rats | |
dc.subject | Neuroblastoma | |
dc.subject | Lactams, Macrocyclic | |
dc.subject | Pyrazoles | |
dc.subject | Pyridines | |
dc.subject | Receptor Protein-Tyrosine Kinases | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Cell Proliferation | |
dc.subject | Mutation | |
dc.subject | Clinical Trials as Topic | |
dc.subject | N-Myc Proto-Oncogene Protein | |
dc.subject | Crizotinib | |
dc.subject | Anaplastic Lymphoma Kinase | |
dc.title | The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-07-04 | |
rioxxterms.versionofrecord | 10.1242/dmm.024448 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Disease models & mechanisms | |
pubs.issue | 9 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.publication-status | Published | |
pubs.volume | 9 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Paediatric Solid Tumour Biology and Therapeutics | |
icr.researchteam | Pre-Clinical MRI | |
dc.contributor.icrauthor | Jamin, Yann | |
dc.contributor.icrauthor | Robinson, Simon | |
dc.contributor.icrauthor | Chesler, Louis | |