High-risk neuroblastoma with NF1 loss of function is targetable using SHP2 inhibition

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 crit-ical 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.

Automated summary

Reoccurring/high-risk neuroblastoma (NB) tumors have non-RAS/RAF mutations along the MAPK signaling pathway, indicating the importance of MEK/ERK activation for their survival. However, MEK inhibitors are unlikely to be effective in NB based on preclinical data and have dose-limiting toxicities. In this study, the allosteric SHP2 inhibitor SHP099 demonstrated high sensitivity in NB models, especially those with low expression of neurofibromin 1 (NF1), a RAS GTPase activation protein (GAP). NF1 expression is lower in advanced and relapsed NB, and NF1 loss is common in high-risk NB tumors. SHP2 inhibition consistently blocked tumor growth in high-risk NB mouse models, revealing a new drug target for relapsed NB.