Targeting the FBXL12-FANCD2 Pathway Disrupts Replication Stress Tolerance in MYCN-Driven Neuroblastoma

High-risk neuroblastoma, a subtype marked by MYCN amplification, showcases a resilience to replication stress that has long eluded researchers. However, a recent investigation sheds light on a MYCN-FBXL12-FANCD2 pathway, a potential therapeutic target, offering insight into how these aggressive cells manage this stress and evade apoptosis.

The study reveals that FBXL12, a SCF ubiquitin ligase substrate receptor responsible for tagging the Fanconi anaemia protein FANCD2 for degradation at replication forks, is significantly upregulated in high-risk and MYCN-amplified neuroblastoma cells. This elevation, independent of other factors, correlates with a grim prognosis for patients.

Furthermore, suppression of FBXL12 allows FANCD2 to remain chromatin-bound, reducing ATR-dependent replication stress signalling and DNA damage during the S phase. This stabilization of FANCD2 hampers the proliferation of MYCN-amplified neuroblastoma cells both in vitro and in vivo.

The study further unravels the mechanism whereby MYCN activates the FBXL12-FANCD2 complex, preventing the ubiquitin-mediated degradation of FANCD2 at replication forks. This action serves a dual purpose: it maintains the chromatin-bound FANCD2 pool needed to withstand replication stress and preserves MYCN's oncogenic drive.

However, beyond the S phase, the loss of FBXL12 disrupts FANCD2-dependent mitotic DNA synthesis, allowing replication intermediates to propagate into daughter cells, potentially triggering genomic instability. As a result, FBXL12-deficient cells exhibit an upregulation of MYC target genes, ATR, and mTOR signalling pathways, making them more susceptible to ATR and mTOR-targeting compounds.

This discovery paves the way for targeted therapies aimed at exploiting this MYCN-FBXL12-FANCD2 axis as a vulnerability in high-risk neuroblastoma.