Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 433, Issue 19, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2021.167158
Keywords
BirA*; signaling; SHP099; RMC-4550; lorlatinib
Categories
Funding
- Swedish Cancer Society [RHP CAN18/729, BH CAN18/718]
- Swedish Childhood Cancer Foundation [PR2019-0078, TJ20160088, PR2016-0011, PR2019-0118]
- Swedish Research Council [RHP 2019-03914]
- Swedish Foundation for Strategic Research [RB13-0204]
- Goran Gustafsson Foundation [RHP2016]
- Knut and Alice Wallenberg Foundation [KAW 2018.0057]
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The study identified interacting proteins of ALK in NB cells and confirmed the ALK-SHP2 interaction, demonstrating that the interaction and SHP2-Y542 phosphorylation are dependent on ALK activation. Inhibition of SHP2 in ALK-driven NB cells resulted in inhibited cell growth, and there was a strong synergistic effect of combined ALK and SHP2 inhibition specific to ALK-driven NB cells, suggesting a potential therapeutic option.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is mutated in approximately 10% of pediatric neuroblastoma (NB). To shed light on ALK-driven signaling processes, we employed BioID-based in vivo proximity labeling to identify molecules that interact intracellularly with ALK. NBderived SK-N-AS and SK-N-BE(2) cells expressing inducible ALK-BirA* fusion proteins were generated and stimulated with ALKAL ligands in the presence and absence of the ALK tyrosine kinase inhibitor (TKI) lorlatinib. LC/MS-MS analysis identified multiple proteins, including PEAK1 and SHP2, which were validated as ALK interactors in NB cells. Further analysis of the ALK-SHP2 interaction confirmed that the ALK-SHP2 interaction as well as SHP2-Y542 phosphorylation was dependent on ALK activation. Use of the SHP2 inhibitors, SHP099 and RMC-4550, resulted in inhibition of cell growth in ALK-driven NB cells. In addition, we noted a strong synergistic effect of combined ALK and SHP2 inhibition that was specific to ALK-driven NB cells, suggesting a potential therapeutic option for ALK-driven NB. (C) 2021 The Author(s). Published by Elsevier Ltd.
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