1. High-risk neuroblastoma with NF1 loss of function is targetable using SHP2 inhibition
- Author
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Jinyang Cai, Sheeba Jacob, Richard Kurupi, Krista M. Dalton, Colin Coon, Patricia Greninger, Regina K. Egan, Giovanna T. Stein, Ellen Murchie, Joseph McClanaghan, Yuta Adachi, Kentaro Hirade, Mikhail Dozmorov, John Glod, Sosipatros A. Boikos, Hiromichi Ebi, Huaixiang Hao, Giordano Caponigro, Cyril H. Benes, and Anthony C. Faber
- Subjects
Mitogen-Activated Protein Kinase Kinases ,Mice ,Neuroblastoma ,Neurofibromin 1 ,Cell Line, Tumor ,Animals ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Mitogen-Activated Protein Kinases ,Neoplasm Recurrence, Local ,Protein Kinase Inhibitors ,General Biochemistry, Genetics and Molecular Biology - Abstract
Reoccurring/high-risk neuroblastoma (NB) tumors have the enrichment of non-RAS/RAF mutations along the mitogen-activated protein kinase (MAPK) signaling pathway, suggesting that activation of MEK/ERK is critical for their survival. However, based on preclinical data, MEK inhibitors are unlikely to be active in NB and have demonstrated dose-limiting toxicities that limit their use. Here, we explore an alternative way to target the MAPK pathway in high-risk NB. We find that NB models are among the most sensitive among over 900 tumor-derived cell lines to the allosteric SHP2 inhibitor SHP099. Sensitivity to SHP099 in NB is greater in models with loss or low expression of the RAS GTPase activation protein (GAP) neurofibromin 1 (NF1). Furthermore, NF1 is lower in advanced and relapsed NB and NF1 loss is enriched in high-risk NB tumors regardless of MYCN status. SHP2 inhibition consistently blocks tumor growth in high-risk NB mouse models, revealing a new drug target in relapsed NB.
- Published
- 2022
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