The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status.
Anaplastic Lymphoma Kinase
/ antagonists & inhibitors
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
Organophosphorus Compounds
/ therapeutic use
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-pim-1
/ antagonists & inhibitors
Pyrimidines
/ pharmacology
Sulfones
/ pharmacology
Thiazolidines
/ pharmacology
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
28 11 2019
28 11 2019
Historique:
received:
05
02
2019
accepted:
04
11
2019
entrez:
30
11
2019
pubmed:
30
11
2019
medline:
3
3
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31780656
doi: 10.1038/s41467-019-13315-x
pii: 10.1038/s41467-019-13315-x
pmc: PMC6883072
doi:
Substances chimiques
AZD1208
0
Biphenyl Compounds
0
MYCN protein, human
0
N-Myc Proto-Oncogene Protein
0
Organophosphorus Compounds
0
Protein Kinase Inhibitors
0
Pyrimidines
0
Sulfones
0
Thiazolidines
0
ALK protein, human
EC 2.7.10.1
Anaplastic Lymphoma Kinase
EC 2.7.10.1
PIM1 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-pim-1
EC 2.7.11.1
brigatinib
HYW8DB273J
ceritinib
K418KG2GET
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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