Maintenance of p-eIF2alpha levels by the eIF2B complex is vital for colorectal cancer

Protein synthesis is an essential process, deregulated in multiple tumor types showing differential dependence on translation factors compared to untransformed tissue. We show that colorectal cancer (CRC) with loss-of-function mutation in the APC tumor suppressor depends on an oncogenic translation program regulated by the ability to sense phosphorylated eIF2a (p-eIF2a). Despite increased protein synthesis rates following APC loss, eIF2a phosphorylation, typically associated with translation inhibition, is enhanced in CRC. Elevated p-eIF2a, and its proper sensing by the decameric eIF2B complex, are essential to balance translation. Knockdown or mutation of eIF2Ba and eIF2Bd, two eIF2B subunits responsible for sensing p-eIF2a, impairs CRC viability, demonstrating that the eIF2B/p-eIF2a nexus is vital for CRC. Specifically, the decameric eIF2B linked by two eIF2Ba subunits is critical for translating growth-promoting mRNAs which are induced upon APC loss. Depletion of eIF2Ba in APC-deficient murine and patient-derived organoids establishes a therapeutic window, validating eIF2Ba as a target for clinical intervention. In conclusion, we demonstrate how expression of the oncogenic signature in CRC is crucially controlled at the translational level.