Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5

TLDR

Cancer cells frequently rewire metabolism to support growth, but this rewiring can create therapeutic vulnerabilities, such as altered methionine metabolism seen in many tumors lacking MTAP. The study proposes that PRMT5 inhibitors could serve as targeted therapy for MTAP‑deficient cancers. Loss of MTAP sensitizes cancer cells to growth inhibition by PRMT5‑targeting compounds. See Mavrakis et al.

Abstract

Tumors put in a vulnerable position Cancer cells often display alterations in metabolism that help fuel their growth. Such metabolic “rewiring” may also work against the cancer cells, however, by creating new vulnerabilities that can be exploited therapeutically. A variety of human tumors show changes in methionine metabolism caused by loss of the gene coding for 5-methylthioadenosine phosphorylase (MTAP). Mavrakis et al. and Kryukov et al. found that the loss of MTAP renders cancer cell lines sensitive to growth inhibition by compounds that suppress the activity of a specific arginine methyltransferase called PRMT5. Conceivably, drugs that inhibit PRMT5 activity could be developed into a tailored therapy for MTAP-deficient tumors. Science , this issue pp. 1208 and 1214