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Type of publication: Journal Article
Type of document: Full Paper

Year: 2019

Authors: Trigg, RM; Lee, LC; Prokoph, N; Jahangiri, L; Reynolds, CP; Amos Burke, GA; Probst, NA; Han, M; Matthews, JD; Lim, HK; Manners, E; Martinez, S; Pastor, J; Blanco-Aparicio, C; Merkel, O; de Los Fayos Alonso, IG; Kodajova, P; Tangermann, S; Högler, S; Luo, J; Kenner, L; Turner, SD

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

Source: Nat Commun. 2019; 10(1):5428



Authors Vetmeduni Vienna:

Högler Sandra
Kenner Lukas
Tangermann Simone

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals


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.

Keywords Pubmed: Anaplastic Lymphoma Kinaseantagonists & inhibitorsgenetics
Animals
Apoptosisdrug effects
Biphenyl Compoundspharmacology
Cell Line, Tumor
Drug Resistance, Neoplasmgenetics
Gene Knockdown Techniques
Humans
Mice
N-Myc Proto-Oncogene Proteingenetics
Neuroblastomadrug therapygenetics
Organophosphorus Compoundstherapeutic use
Protein Kinase Inhibitorspharmacologytherapeutic use
Proto-Oncogene Proteins c-pim-1antagonists & inhibitorsgenetics
Pyrimidinespharmacologytherapeutic use
Sulfonespharmacologytherapeutic use
Thiazolidinespharmacology
Xenograft Model Antitumor Assays

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