Research ArticleCancer

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

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Science Signaling  17 Nov 2015:
Vol. 8, Issue 403, pp. ra116
DOI: 10.1126/scisignal.aad5111

Targeting drug-resistant prostate tumors

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.

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