Cell type–specific abundance of 4EBP1 primes prostate cancer sensitivity or resistance to PI3K pathway inhibitors

The activity of the PI3K-AKT-mTOR signaling pathway is often increased in various cancer types. Unfortunately, the development of resistance to PI3K pathway inhibitors is common. In a transgenic mouse model of prostate cancer, Hsieh et al. found that cell type–specific resistance was mediated by the abundance of 4EBP1, an mTOR target that inhibits protein synthesis. Compared with basal cells, luminal prostate epithelial cells had increased expression of 4EBP1, decreased protein synthesis rates, and decreased sensitivity to the mTOR inhibitor MLN0128. In both mice and patients with prostate cancer, treatment with a PI3K pathway inhibitor increased the proportion of luminal tumor cells that had high abundance of 4EBP1. Because decreasing 4EBP1 abundance suppressed resistance to MLN0128, the findings suggest that co-targeting 4EBP1 may improve therapeutic outcomes for prostate cancer patients.Pharmacological inhibitors against the PI3K-AKT-mTOR (phosphatidylinositol 3-kinase–AKT–mammalian target of rapamycin) pathway, a frequently deregulated signaling pathway in cancer, are clinically promising, but the development of drug resistance is a major limitation. We found that 4EBP1, the central inhibitor of cap-dependent translation, was a critical regulator of both prostate cancer initiation and maintenance downstream of mTOR signaling in a genetic mouse model. 4EBP1 abundance was distinctly different between the epithelial cell types of the normal prostate. Of tumor-prone prostate epithelial cell types, luminal epithelial cells exhibited the highest transcript and protein abundance of 4EBP1 and the lowest protein synthesis rates, which mediated resistance to both pharmacologic and genetic inhibition of the PI3K-AKT-mTOR signaling pathway. Decreasing total 4EBP1 abundance reversed resistance in drug-insensitive cells. Increased 4EBP1 abundance was a common feature in prostate cancer patients who had been treated with the PI3K pathway inhibitor BKM120; thus, 4EBP1 may be associated with drug resistance in human tumors. Our findings reveal a molecular program controlling cell type–specific 4EBP1 abundance coupled to the regulation of global protein synthesis rates that renders each epithelial cell type of the prostate uniquely sensitive or resistant to inhibitors of the PI3K-AKT-mTOR signaling pathway.