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

Ricky M. Trigg, Liam C. Lee, Nina Prokoph, Leila Jahangiri, C. Patrick Reynolds, G. A. Amos Burke, Nicola A. Probst, Miaojun Han, Jamie D. Matthews, Hong Kai Lim, Eleanor Manners, Sonia Martinez, Joaquin Pastor, Carmen Blanco-Aparicio, Olaf Merkel, Ines Garces los Fayos Alonso, Petra Kodajova, Simone Tangermann, Sandra Högler, Ji Luo, Lukas Kenner and Suzanne D. Turner ()
Additional contact information
Ricky M. Trigg: University of Cambridge
Liam C. Lee: University of Cambridge
Nina Prokoph: University of Cambridge
Leila Jahangiri: University of Cambridge
C. Patrick Reynolds: Cancer Center, Texas Tech University Health Sciences Center School of Medicine
G. A. Amos Burke: Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus
Nicola A. Probst: University of Cambridge
Miaojun Han: University of Cambridge
Jamie D. Matthews: University of Cambridge
Hong Kai Lim: University of Cambridge
Eleanor Manners: University of Cambridge
Sonia Martinez: Spanish National Cancer Research Centre (CNIO)
Joaquin Pastor: Spanish National Cancer Research Centre (CNIO)
Carmen Blanco-Aparicio: Spanish National Cancer Research Centre (CNIO)
Olaf Merkel: Medical University of Vienna
Ines Garces los Fayos Alonso: Medical University of Vienna
Petra Kodajova: University of Veterinary Medicine Vienna
Simone Tangermann: University of Veterinary Medicine Vienna
Sandra Högler: University of Veterinary Medicine Vienna
Ji Luo: National Cancer Institute, National Institutes of Health
Lukas Kenner: Medical University of Vienna
Suzanne D. Turner: University of Cambridge

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13315-x

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