2026-06-14T14:07:31Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/92982024-11-29T14:29:57Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc 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 author 2019-11-28 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. 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 The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status