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

Accepted version
Peer-reviewed

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Authors

Lee, Liam C 
Prokoph, Nina 
Jahangiri, Leila 
Reynolds, C Patrick 

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.

Description

Keywords

Anaplastic Lymphoma Kinase, Animals, Apoptosis, Biphenyl Compounds, Cell Line, Tumor, Drug Resistance, Neoplasm, Gene Knockdown Techniques, Humans, Mice, N-Myc Proto-Oncogene Protein, Neuroblastoma, Organophosphorus Compounds, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-pim-1, Pyrimidines, Sulfones, Thiazolidines, Xenograft Model Antitumor Assays

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

10

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Children with Cancer UK (16-209)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (675712)
This research is supported with funding from Children with Cancer UK (CWCUK; 16-209) awarded to SDT and LCL, RMT was supported by the CWCUK grant and LCL was in receipt of a Cancer Research UK Cambridge Centre Paediatric Programme PhD studentship. NP, LJ, OM, IGFA, LK, and SDT are supported by a European Union Horizon 2020 Marie Skłodowska-Curie Innovative Training Networks (ITN-ETN) Grant, Grant No.: 675712. NAP was supported by ERASMUS+.