Background: Medulloblastoma (MB) consists of four major molecular subtypes and group 3 subtype (G3) is the most aggressive one. MYC amplification tends to happen in G3 MB and those patients exhibit the worse prognosis and need novel effective therapeutic approach most urgently. MYC has been shown to be the driver as well as crucial dependency for MYC-amplified G3-MB, thus serving as a promising therapeutic target.
Methods: In this study, we tested inhibiting MYC translation in MYC-amplified G3-MB by targeting eIF4F complex. We analyzed multiple MB tumor data sets to identify potential therapeutic target of eIF4F components and utilized genetic or pharmacological approaches for validation. The relevant inhibitory mechanisms were further investigated by Western blot and whole lysate mass spectrometry assays to confirm the targeting of MYC translation.
Results: Tumor data set analyses identified eIF4A1, a subunit of eIF4F complex, which was significantly upregulated in G3-MB compared to normal cerebellum and highly correlated with MYC at transcript level. Targeting eIF4A1 with CRISPR/Cas9 approach or small-molecule inhibitor Silvestrol effectively attenuated growth of multiple preclinical models through blocking proliferation and inducing apoptosis. Mechanistically, Silvestrol treatment effectively inhibited MYC expression at protein level and MYC amplification was shown to sensitize MB cells to eIF4A1 inhibition. Moreover, whole proteome mass spectrometry analyses demonstrated additional biological functions or pathways affected by eIF4A1 inhibition, which could help in better understanding its inhibitory mechanisms and revealing combinatory strategies.
Conclusion: It is shown in our study that targeting MYC translation by eIF4A1 inhibition could be an effective therapeutic strategy against MYC-amplified G3-MB.