Zeitschriftenaufsatz
|
2019
The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status
Autor:in
Trigg, Ricky; Lee, Liam; Prokoph, Nina; Jahangiri, Leila; Reynolds, Patrick; Burke, Amos; Probst, Nicola A.; Han, Miao; Matthews, Jamie D.; Lim, Hong Kai; Manners, Eleanor; Martinez Gonzalez, Sonia; Fernandez, Joaquin; Blanco-Aparicio, Carmen; Merkel, Olaf; Alonso, Ines Garces De Los Fayos; Kodajova, Petra; Tangermann, Simone; Hoegler, Sandra; Luo, Ji; Kenner, Lukas; Turner, Suzanne
Publikationen als Autor:in / Herausgeber:in der Vetmeduni
Journal
Abstrakt
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.
Schlagwörter
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
Dokumententyp
Originalarbeit
CC Lizenz
CCBY
Open Access Type
Gold
ISSN/eISSN
2041-1723 -
10.1038/s41467-019-13315-x
WoS ID
PubMed ID