A MYC/GCN2/eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer

Tumours depend on altered rates of protein synthesis for growth and survival, suggesting that mechanisms controlling mRNA translation may be exploitable for therapy. Here, we show that loss of APC, which occurs almost universally in colorectal tumours, strongly enhances the dependence on the translation initiation factor eIF2B5. Depletion of eIF2B5 induces an integrated stress response and enhances translation of MYC via an internal ribosomal entry site. This perturbs cellular amino acid and nucleotide pools and strains energy resources and causes MYC-dependent apoptosis. eIF2B5 limits MYC expression and prevents apoptosis in APC-deficient murine and patient-derived organoids and in APC-deficient murine intestinal epithelia in vivo. Conversely, the high MYC levels present in APC-deficient cells induce phosphorylation of eIF2α via the GCN2 and PKR kinases. Pharmacological inhibition of GCN2 phenocopies eIF2B5 depletion and has therapeutic efficacy in tumour organoids, demonstrating that a negative MYC/eIF2α feedback loop constitutes a targetable vulnerability of colorectal tumours.