Growth factor signaling predicts therapy resistance mechanisms and defines neuroblastoma subtypes

Timofey Lebedev,Maria Suntsova,Elmira Vagapova,Alexander Roumiantsev,Pavel Spirin,Anton Buzdin,Uliana Vladimirova,Olga Astashkova,Alesya Mikheeva,Vladimir Prassolov,Carol Stocking,Dmitry Konovalov,Petr Rubtsov,Maxim Sorokin

doi:10.1038/s41388-021-02018-7

Abstract

Neuroblastoma (NB) has a low frequency of recurrent mutations compared to other cancers, which hinders the development of targeted therapies and novel risk stratification strategies. Multikinase inhibitors have shown potential in treating high-risk NB, but their efficacy is likely impaired by the cancer cells’ ability to adapt to these drugs through the employment of alternative signaling pathways. Based on the expression of 48 growth factor-related genes in 1189 NB tumors, we have developed a model for NB patient survival prediction. This model discriminates between stage 4 NB tumors with favorable outcomes (>80% overall survival) and very poor outcomes (<10%) independently from MYCN-amplification status. Using signaling pathway analysis and gene set enrichment methods in 60 NB patients with known therapy response, we identified signaling pathways, including EPO, NGF, and HGF, upregulated in patients with no or partial response. In a therapeutic setting, we showed that among six selected growth factors, EPO, and NGF showed the most pronounced protective effects in vitro against several promising anti-NB multikinase inhibitors: imatinib, dasatinib, crizotinib, cabozantinib, and axitinib. Mechanistically kinase inhibitors potentiated NB cells to stronger ERK activation by EPO and NGF. The protective action of these growth factors strongly correlated with ERK activation and was ERK-dependent. ERK inhibitors combined with anticancer drugs, especially with dasatinib, showed a synergistic effect on NB cell death. Consideration of growth factor signaling activity benefits NB outcome prediction and tailoring therapy regimens to treat NB.

Highlights

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor and is responsible for ~8% of all childhood cancer cases [1]
Our study shows that the expression of cellular receptors and their downstream kinases can define NB subtypes which have a distinct association with patient survival
We show that this model can be used to discriminate patients with stage 4 tumors without MYCN-amplification into patients, for whom current treatment will work well with survival >90% and for whom standard therapy will probably fail with survival probability

Summary

Introduction

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor and is responsible for ~8% of all childhood cancer cases [1]. Cluster 3 had the lowest percentage of MYCN Activated growth factor signaling is associated with amplified tumors (1%) (Fig. S1a, b) and had a high expression of metastasis, poor outcome, and relapse incidence in NB To calculate association of signaling pathways with therapy response and metastasis we used gene expression profiles for 60 NB, ganglioneuroma, and prognosis, and patients in cluster 3 had a very favorable prognosis ganglioneuroblastoma tumors (41 samples from previously (Fig. S1c).

Results

Conclusion