Abstract
The navigation cue netrin‐1 is well‐documented for its key role in cancer development and represents a promising therapeutic target currently under clinical investigation. Phase 1 and 2 clinical trials are ongoing with NP137, a humanized monoclonal antibody against netrin‐1. Interestingly, the epitope recognized by NP137 in netrin‐1 shares 90% homology with its counterpart in netrin‐3, the closest member to netrin‐1 in humans, for which little is known in the field of cancer. Here, we unveiled that netrin‐3 appears to be expressed specifically in human neuroblastoma (NB) and small cell lung cancer (SCLC), two subtypes of neuroectodermal/neuroendocrine lineages. Netrin‐3 and netrin‐1 expression are mutually exclusive, and the former is driven by the MYCN oncogene in NB, and the ASCL‐1 or NeuroD1 transcription factors in SCLC. Netrin‐3 expression is correlated with disease stage, aggressiveness, and overall survival in NB. Mechanistically, we confirmed the high affinity of netrin‐3 for netrin‐1 receptors and we demonstrated that netrin‐3 genetic silencing or interference using NP137, delayed tumor engraftment, and reduced tumor growth in animal models. Altogether, these data support the targeting of netrin‐3 in NB and SCLC.
Highlights
Navigation cues such as semaphorins, netrins, or ephrins have been shown to play various crucial roles in many cellular processes (Stoeckli, 2018)
Compared to netrin-1 gene expression, which is displayed by most cancers, netrin-3 gene expression was largely represented by two specific clusters corresponding to neuroblastoma (NB) and small cell lung cancer (SCLC) (Fig 1A)
While netrin-1 was detectable (FPKM ≥ 1) in 43.3% of cell lines, netrin-3 was only detected in 4.8%, and their common expression occurred in only 0.015% of cell lines (P = 0.037—Fisher’s exact test) (Fig 1C), arguing in favor of a selective event driving high netrin-3 gene expression in these two neuroepithelial cancer indications (Rindi et al, 2018)
Summary
Navigation cues such as semaphorins, netrins, or ephrins have been shown to play various crucial roles in many cellular processes (Stoeckli, 2018). Members of the netrin family, strongly implicated in the nervous system development, have been associated with several pathologies (van Gils et al, 2012; Ramkhelawon et al, 2014; Renders et al, 2021). An effort to assay the clinical relevance of inhibiting netrin-1/receptor interactions is currently ongoing with an anti-netrin-1 monoclonal antibody NP137 (Grandin et al, 2016). Preliminary data from the phase 1 trial performed on patients with advanced solid cancer have recently been presented, underlining an encouraging anti-tumor activity (Cassier et al, 2019). A phase-1b/2 trial investigating NP137 in combination with chemotherapy or/and anti-PD1 in a specific a 2021 The Authors.
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