2026-06-14T14:07:32Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/92982024-11-29T14:29:57Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Trigg, Ricky M
author
Lee, Liam C
author
Prokoph, Nina
author
Jahangiri, Leila
author
Reynolds, C Patrick
author
Amos Burke, G A
author
Probst, Nicola A
author
Han, Miaojun
author
Matthews, Jamie D
author
Lim, Hong Kai
author
Manners, Eleanor
author
Martinez, Sonia
author
Pastor Fernandez, Joaquin
author
Blanco-Aparicio, Carmen
author
Merkel, Olaf
author
Garces de Los Fayos Alonso, Ines
author
Kodajova, Petra
author
Tangermann, Simone
author
Högler, Sandra
author
Luo, Ji
author
Kenner, Lukas
author
Turner, Suzanne D
funder
Children with Cancer UK
funder
Cancer Research UK (Reino Unido)
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
2020-03-20T19:34:33Z
2020-03-20T19:34:33Z
2019-11-28
Nat Commun. 2019 Nov 28;10(1):5428.
10.1038/s41467-019-13315-x
2041-1723
2041-1723
Nature communications
31780656
http://hdl.handle.net/20.500.12105/9298
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.
eng
The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status
journal article
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