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High-risk neuroblastoma with NF1 loss of function is targetable using SHP2 inhibition
Jinyang Cai1, Sheeba Jacob1, Richard Kurupi1
1Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
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.
Insights
High-risk neuroblastoma (NB) shows sensitivity to SHP2 inhibition, offering a new therapeutic strategy. Targeting SHP2, particularly in tumors with neurofibromin 1 (NF1) loss, effectively blocks tumor growth in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Signal Transduction
Background:
- High-risk neuroblastoma (NB) tumors often feature mutations in the mitogen-activated protein kinase (MAPK) pathway, specifically non-RAS/RAF mutations.
- Activation of MEK/ERK signaling is crucial for NB cell survival, but MEK inhibitors show limited efficacy and dose-limiting toxicities in NB.
- Targeting the MAPK pathway remains a critical challenge in treating relapsed and high-risk neuroblastoma.
Purpose of the Study:
- To investigate alternative strategies for targeting the MAPK pathway in high-risk neuroblastoma.
- To evaluate the efficacy of the allosteric SHP2 inhibitor SHP099 in NB models.
- To identify predictive biomarkers for SHP099 sensitivity in neuroblastoma.
Main Methods:
- Screening of over 900 tumor-derived cell lines to identify sensitivity to SHP099.
- Assessing SHP099 sensitivity in NB models with varying neurofibromin 1 (NF1) expression levels.
- Evaluating tumor growth inhibition in high-risk NB mouse models treated with SHP099.
Main Results:
- Neuroblastoma models demonstrated significant sensitivity to the SHP2 inhibitor SHP099.
- Sensitivity to SHP099 was enhanced in NB models with loss or low expression of neurofibromin 1 (NF1).
- NF1 loss was found to be enriched in advanced, relapsed, and high-risk NB tumors, irrespective of MYCN status.
Conclusions:
- SHP2 inhibition represents a promising therapeutic strategy for high-risk and relapsed neuroblastoma.
- NF1 status can serve as a predictive biomarker for response to SHP2 inhibitors in NB.
- Targeting SHP2 offers a novel approach to overcome resistance mechanisms in neuroblastoma treatment.
