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

Trigg, Ricky M and Lee, Liam and Prokoph, Nina and Jahangiri, Leila and Reynolds, C. Patrick and Burke, G. A. Amos and Probst, Nicola A and Han, Miaojun and Matthews, Jamie and Kai Lim, Hong and Manners, Eleanor and Martinez, Sonia and Pastor, Joaquin and Blanco-Aparicio, Carmen and Merkel, Olaf and Garces de los Fayos Alonso, Ines and Kodajova, Petra and Tangermann, Simone and Högler, Sandra and Luo, Ji and Kenner, Lukas and Turner, Suzanne D (2019) The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status. Nature communications, 10. ISSN 2041-1723

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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.

Item Type:	Article
Identification Number:	10.1038/s41467-019-13315-x
Dates:	Date Event 28 November 2019 Published 1 November 2019 Accepted
Uncontrolled Keywords:	Cancer models, Cancer therapeutic resistance, Paediatric cancer, Targeted therapies
Subjects:	CAH01 - medicine and dentistry > CAH01-01 - medicine and dentistry > CAH01-01-01 - medical sciences (non-specific)
Divisions:	Faculty of Health, Education and Life Sciences > College of Health and Care Professions
Depositing User:	Leila Jahangiri
Date Deposited:	07 Jan 2020 13:02
Last Modified:	12 Jan 2022 11:12
URI:	https://www.open-access.bcu.ac.uk/id/eprint/8672

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