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

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

Author information

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. sdt36@cam.ac.uk.

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.

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