Trigg, Ricky MLee, Liam CProkoph, NinaJahangiri, LeilaReynolds, C PatrickAmos Burke, G AProbst, Nicola AHan, MiaojunMatthews, Jamie DLim, Hong KaiManners, EleanorMartinez, SoniaPastor Fernandez, JoaquinBlanco-Aparicio, CarmenMerkel, OlafGarces de Los Fayos Alonso, InesKodajova, PetraTangermann, SimoneHögler, SandraLuo, JiKenner, LukasTurner, Suzanne D2020-03-202020-03-202019-11-28Nat Commun. 2019 Nov 28;10(1):5428.2041-1723http://hdl.handle.net/20.500.12105/9298Resistance 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.engVoRhttp://creativecommons.org/licenses/by-nc-sa/4.0/Anaplastic Lymphoma KinaseAnimalsApoptosisBiphenyl CompoundsCell Line, TumorDrug Resistance, NeoplasmGene Knockdown TechniquesHumansMiceN-Myc Proto-Oncogene ProteinNeuroblastomaOrganophosphorus CompoundsProtein Kinase InhibitorsProto-Oncogene Proteins c-pim-1PyrimidinesSulfonesThiazolidinesXenograft Model Antitumor AssaysAtribución-NoComercial-CompartirIgual 4.0 Internacional31780656101542810.1038/s41467-019-13315-x2041-1723Nature communicationsopen access