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
  • 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 [email protected] [email protected] [email protected].
  • 8. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg SE-405 30, Sweden [email protected] [email protected] [email protected].
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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