Format

Send to

Choose Destination
Dis Model Mech. 2016 Sep 1;9(9):941-52. doi: 10.1242/dmm.024448. Epub 2016 Jul 7.

The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.

Author information

1
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden.
2
Division of Clinical Studies Cancer Therapeutics, The Institute of Cancer Research, London and Royal Marsden NHS Foundation Trust, Sutton SM2 5NG, UK.
3
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden Department of Molecular Biology, Building 6L, Umeå University, Umeå 901 87, Sweden.
4
Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and Royal Marsden NHS Foundation Trust, Sutton SM2 5NG, UK.
5
La Jolla Laboratories, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
6
Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden.
7
Division of Clinical Studies Cancer Therapeutics, The Institute of Cancer Research, London and Royal Marsden NHS Foundation Trust, Sutton SM2 5NG, UK louis.chesler@icr.ac.uk ruth.palmer@gu.se bengt.hallberg@gu.se.
8
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden louis.chesler@icr.ac.uk ruth.palmer@gu.se bengt.hallberg@gu.se.

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.

KEYWORDS:

ALK; Lorlatinib; MYCN; Mouse models; Neuroblastoma; PF-06463922

PMID:
27483357
PMCID:
PMC5047689
DOI:
10.1242/dmm.024448
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

T.W.J. and T.S. are employees and shareholders of Pfizer Inc. The authors declare no other competing or financial interests.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center