The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

Ricky M Trigg; Liam C Lee; Nina Prokoph; Leila Jahangiri; C Patrick Reynolds; G A Amos Burke; Nicola A Probst; Miaojun Han; Jamie D Matthews; Hong Kai Lim; Eleanor Manners; Sonia Martinez; Joaquin Pastor; Carmen Blanco-Aparicio; Olaf Merkel; Ines Garces de Los Fayos Alonso; Petra Kodajova; Simone Tangermann; Sandra Högler; Ji Luo; Lukas Kenner; Suzanne D Turner

doi:10.1038/s41467-019-13315-x

The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

Nat Commun. 2019 Nov 28;10(1):5428. doi: 10.1038/s41467-019-13315-x.

Authors

Ricky M Trigg^{1

2}, Liam C Lee^{1

3}, Nina Prokoph¹, Leila Jahangiri¹, C Patrick Reynolds⁴, G A Amos Burke⁵, Nicola A Probst¹, Miaojun Han^{1

6}, Jamie D Matthews¹, Hong Kai Lim¹, Eleanor Manners¹, Sonia Martinez⁷, Joaquin Pastor⁷, Carmen Blanco-Aparicio⁷, Olaf Merkel⁸, Ines Garces de Los Fayos Alonso⁸, Petra Kodajova⁹, Simone Tangermann⁹, Sandra Högler⁹, Ji Luo¹⁰, Lukas Kenner^{8

9

11}, Suzanne D Turner¹²

Affiliations

¹ Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Lab Block level 3, Box 231, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
² Functional Genomics, Medicinal Science & Technology, GlaxoSmithKline, Stevenage, SG1 2NY, UK.
³ Amgen, Thousand Oaks, CA, 91320, USA.
⁴ Cancer Center, Texas Tech University Health Sciences Center School of Medicine, Lubbock, TX, 79430, USA.
⁵ Department of Paediatric Oncology, Box 181, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK.
⁶ OncoSec, San Diego, CA, 92121, USA.
⁷ Experimental Therapeutics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
⁸ Department of Experimental Pathology and Laboratory Animal Pathology, Institute of Clinical Pathology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, 1090, Austria.
⁹ Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Veterinärplatz 1, Vienna, 1210, Austria.
¹⁰ Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA.
¹¹ Christian Doppler Laboratory for Applied Metabolomics (CDL-AM), Boltzmanngasse 20, Medical University of Vienna, Vienna, 1090, Austria.
¹² Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Lab Block level 3, Box 231, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. [email protected].

Abstract

Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anaplastic Lymphoma Kinase / antagonists & inhibitors*
Anaplastic Lymphoma Kinase / genetics
Animals
Apoptosis / drug effects
Biphenyl Compounds / pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics*
Gene Knockdown Techniques
Humans
Mice
N-Myc Proto-Oncogene Protein / genetics
Neuroblastoma / drug therapy
Neuroblastoma / genetics*
Organophosphorus Compounds / therapeutic use
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors
Proto-Oncogene Proteins c-pim-1 / genetics*
Pyrimidines / pharmacology
Pyrimidines / therapeutic use
Sulfones / pharmacology
Sulfones / therapeutic use
Thiazolidines / pharmacology
Xenograft Model Antitumor Assays

Substances

AZD1208
Biphenyl Compounds
MYCN protein, human
N-Myc Proto-Oncogene Protein
Organophosphorus Compounds
Protein Kinase Inhibitors
Pyrimidines
Sulfones
Thiazolidines
ALK protein, human
Anaplastic Lymphoma Kinase
PIM1 protein, human
Proto-Oncogene Proteins c-pim-1
brigatinib
ceritinib