1. The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status
- Author
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Petra Kodajova, Sonia Sánchez Martínez, Nicola A. Probst, Liam C. Lee, Ines Garces de los Fayos Alonso, Miaojun Han, Sandra Högler, Joaquín Pastor, G. A. Amos Burke, C. Patrick Reynolds, Hong Kai Lim, Eleanor Manners, Carmen Blanco-Aparicio, Leila Jahangiri, Jamie D. Matthews, Ji Luo, Suzanne D. Turner, Nina Prokoph, Simone Tangermann, Lukas Kenner, Olaf Merkel, Ricky M Trigg, Trigg, Ricky M. [0000-0001-9329-9344], Martinez, Sonia [0000-0003-2230-7794], Blanco-Aparicio, Carmen [0000-0002-3249-6595], Kenner, Lukas [0000-0003-2184-1338], Turner, Suzanne D. [0000-0002-8439-4507], Apollo - University of Cambridge Repository, Trigg, Ricky M [0000-0001-9329-9344], Turner, Suzanne D [0000-0002-8439-4507], Children with Cancer UK, Cancer Research UK (Reino Unido), and European Research Council
- Subjects
0301 basic medicine ,82/29 ,45/41 ,General Physics and Astronomy ,Apoptosis ,45/47 ,96/31 ,13/2 ,13/1 ,38/1 ,42/47 ,Mice ,Neuroblastoma ,0302 clinical medicine ,42/89 ,hemic and lymphatic diseases ,38/23 ,38/22 ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,Sulfones ,lcsh:Science ,13/89 ,N-Myc Proto-Oncogene Protein ,Multidisciplinary ,Chemistry ,45/77 ,3. Good health ,Biphenyl compound ,13/31 ,Cancer therapeutic resistance ,631/67/1059/602 ,030220 oncology & carcinogenesis ,631/67/2332 ,Gene Knockdown Techniques ,38/77 ,Thiazolidines ,64/60 ,631/67/70 ,82/1 ,medicine.drug ,Brigatinib ,medicine.drug_class ,631/67/1059/2326 ,Science ,49/22 ,49/23 ,PIM1 ,38/90 ,45/22 ,13/106 ,45/23 ,13/109 ,General Biochemistry, Genetics and Molecular Biology ,Article ,96/95 ,Paediatric cancer ,03 medical and health sciences ,Targeted therapies ,Organophosphorus Compounds ,Proto-Oncogene Proteins c-pim-1 ,Cell Line, Tumor ,38/89 ,medicine ,Animals ,Humans ,96/2 ,96/1 ,Cancer models ,Protein Kinase Inhibitors ,38/109 ,96/106 ,Ceritinib ,Biphenyl Compounds ,General Chemistry ,64/110 ,medicine.disease ,Xenograft Model Antitumor Assays ,ALK inhibitor ,030104 developmental biology ,Pyrimidines ,Drug Resistance, Neoplasm ,13/51 ,13/95 ,Cancer research ,lcsh:Q ,82/51 - 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.
- Published
- 2019
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