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

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 e...

Full description

Bibliographic Details
Authors: Trigg, Ricky M, Lee, Liam C, Prokoph, Nina, Jahangiri, Leila, Reynolds, C Patrick, Amos Burke, G A, Probst, Nicola A, Han, Miaojun, Matthews, Jamie D, Lim, Hong Kai, Manners, Eleanor, Martinez, Sonia, Pastor Fernandez, Joaquin, Blanco-Aparicio, Carmen, Merkel, Olaf, Garces de Los Fayos Alonso, Ines, Kodajova, Petra, Tangermann, Simone, Högler, Sandra, Luo, Ji, Kenner, Lukas, Turner, Suzanne D
Format: article
Publication Date:2019
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/9298
Online Access:http://hdl.handle.net/20.500.12105/9298
Access Level:Open access
Keyword: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
Description
Summary: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.

Similar Items