Journal
DISEASE MODELS & MECHANISMS
Volume 9, Issue 9, Pages 941-952Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.024448
Keywords
PF-06463922; Neuroblastoma; ALK; MYCN; Mouse models; Lorlatinib
Categories
Funding
- Swedish Cancer Society (Cancerfonden) [BH 12-0722, RHP 12-0796]
- Children's Cancer Foundation (Barncancerfonden) [BH 11/020, RHP 13/0049]
- Swedish Research Council (Vetenskapsradet) [RHP 621-2011-5181, BH 521-2012-2831]
- Swedish Foundation for Strategic Research (Stiftelsen for Strategisk Forskning) [RB13-0204]
- European Commission [BH 286418]
- Cancer Research UK [A14610, C18339]
- Medical Research Council
- SPARKS Charity Clinical Research Training Fellowship [MRC116X]
- Institute of Cancer Research, Royal Cancer Hospital (ICR, RMH)
- Higher Education Funding Council for England
- Engineering and Physical Sciences Research Council
- Department of Health (England) [C1060/A10334, C1060/A16464]
- NHS
- Paul O'Gorman Postdoctoral Fellowship - Children with Cancer UK
- MRC [G1100386] Funding Source: UKRI
- Swedish Foundation for Strategic Research (SSF) [RB13-0204] Funding Source: Swedish Foundation for Strategic Research (SSF)
- Cancer Research UK [16464, 18339] Funding Source: researchfish
- Medical Research Council [G1100386] Funding Source: researchfish
- Sparks Charity [11MRCRMH14 - DCCF] Funding Source: researchfish
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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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