Lost in translation: Cancer and the regulation of protein synthesis

Protein synthesis is an energy-intensive process, with translation initiation being a key regulatory step. This thesis focuses on the roles of three translation initiation factors in cancer with the aim to identify novel therapeutic targets.
Amplification of the chromosomal region encompassing the initiation factor 4EBP1 created a synthetic dependency on FGFR1 signaling in cancer. This indicates a therapeutic potential for FGFR1 inhibitors by effectively disrupting phosphorylation of 4EBP1. We showed that 4EBP1 plays a role in regulating genes involved in insulin signaling, glucose metabolism, and the inositol pathway, three pathways contributing to cancer progression.
Treatment of sarcomas with the 4EBP1 inhibitor CR-1-31B induced apoptosis and suppressed growth in vitro and in vivo. Ribosome profiling of cells treated with CR-1-31B identified YAP and TAZ as the critical eIF4A-dependent genes.
Inhibitors of the initiation factor eIF4A like silvestrol showed promising results in treating aggressive lymphomas. However, drug resistance arose through MDR1-mediated efflux of sivestrol. A genome-wide CRISPR/Cas9 screen revealed that activation of NRF2 reduced the efficacy of the eIF4A inhibitor. This resistance could be reverted by blocking FN3K which decreased the stability of NRF2.
Using pancreatic cancer models we showed that genes with long, structured 5’UTRs rely on eIF4A for translation. CR-1-31B treatment effectively suppressed tumor growth by disrupting KRAS-dependent translation, reducing KRAS, MYC, and ERK signaling.
In conclusion, our study demonstrates that disrupting translation initiation, particularly through 4EBP1 and eIF4A inhibition, can suppress tumor progression and this offers new therapeutic strategies for cancer.