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- Title
The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status.
- 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.; Kai Lim, Hong; Manners, Eleanor; Martinez, Sonia; Pastor, Joaquin; Blanco-Aparicio, Carmen; Merkel, Olaf; de los Fayos Alonso, Ines Garces; Kodajova, Petra; Tangermann, Simone; Högler, Sandra; Luo, Ji
- 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. Anaplastic lymphoma kinase (ALK) inhibitors are currently being considered in neuroblastoma (NB), but its acquired resistance is reported in non-small cell lung cancers. Here, the authors have found PIM1 overexpression decreases sensitivity to ALK inhibitors in NB and combined ALK and PIM1 inhibition enhances anti-tumour efficacy in vitro and in PDX models.
- Subjects
ANAPLASTIC lymphoma kinase; NON-small-cell lung carcinoma; PROGNOSIS
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-13315-x