The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

• Published in: Nature communications 2019-11, Vol.10 (1), p.5428-13, Article 5428
• Main 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., Lim, Hong Kai, 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, Kenner, Lukas, Turner, Suzanne D.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/31; 13/51; 13/89; 13/95; 38/1; 38/109; 38/22; 38/23; 38/77; 38/89; 38/90; 42/47; 42/89; 45/22; 45/23; 45/41; 45/47; 45/77; 49/22; 49/23; 631/67/1059/2326; 631/67/1059/602; 631/67/2332; 631/67/70; 64/110; 64/60; 82/1; 82/29; 82/51; 96/1; 96/106; 96/2; 96/31; 96/95; Anaplastic Lymphoma Kinase - antagonists & inhibitors; Anaplastic Lymphoma Kinase - genetics; Animals; Anticancer properties; Apoptosis - drug effects; Biphenyl Compounds - pharmacology; Cell activation; Cell Line, Tumor; CRISPR; Drug Resistance, Neoplasm - genetics; Enzyme inhibitors; Gene expression; Gene Knockdown Techniques; Genomes; Health risks; Humanities and Social Sciences; Humans; Inhibitors; Kinases; Lung cancer; Lymphoma; Mice; multidisciplinary; Mutation; N-Myc Proto-Oncogene Protein - genetics; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - genetics; Non-small cell lung carcinoma; Organophosphorus Compounds - therapeutic use; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors; Proto-Oncogene Proteins c-pim-1 - genetics; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Risk; Science; Science (multidisciplinary); Small cell lung carcinoma; Sulfones - pharmacology; Sulfones - therapeutic use; Thiazolidines - pharmacology; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13315-x

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.