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

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

  • Dis Model Mech. 2016 Sep 1;9(9):941-52. doi: 10.1242/dmm.024448.
J Guan 1,  E R Tucker 2,  H Wan 1,  D Chand 1,  L S Danielson 2,  K Ruuth 3,  A El Wakil 3,  B Witek 3,  Y Jamin 4,  G Umapathy 1,  S P Robinson 4,  T W Johnson 5,  T Smeal 5,  T Martinsson 6,  L Chesler 7,  R H Palmer 8,  B Hallberg 8
Affiliations

Affiliations

  • 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.
PMID: 27483357 DOI: 10.1242/dmm.024448
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.

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