In MTAP-deficient cancer cells, PRMT5 expression and activity is preferentially required for cell growth.

  • Major finding: In MTAP-deficient cancer cells, PRMT5 expression and activity is preferentially required for cell growth.

  • Mechanism:MTAP loss results in accumulation of MTA, which inhibits PRMT5 methyltransferase activity.

  • Impact: Inhibition of PRMT5 is a potential therapeutic strategy in tumors with MTAP deletion.

The methionine salvage pathway enzyme 5-methylthioadenosine phosphorylase (MTAP) is deleted in many human tumors across multiple tumor types, including in approximately half of glioblastomas, due to its proximity to the tumor suppressor CDNK2A. In order to identify potential targetable genetic vulnerabilities created by MTAP loss, Mavrakis and colleagues analyzed data from a large-scale shRNA screen of cancer cell lines. This screen identified the protein arginine methyltransferase 5 (PRMT5) as the most significant hit. Knockdown of PRMT5 reduced the growth of pancreatic cancer cell lines and xenografts lacking MTAP, and led to reduced dimethylation of the PRMT5 substrate histone 4 arginine 3. MTAP metabolizes methylthioadenosine (MTA) into adenine and methionine, and MTAP loss led to the accumulation of MTA, which selectively inhibited the methyltransferase activity of PRMT5. Further, the crystal structure of MTA-bound PRMT5 indicated that MTA alters the cofactor binding pocket and competed with S-adenosyl methionine (SAM) for binding to PRMT5. This suggested that MTAP loss sensitized cells to PRMT5 inhibition by altering the ratio of MTA and SAM. In an independent shRNA screen, Kryukov and colleagues also identified PRMT5 as essential for MTAP-deficient cell viability, and observed similar impairment of cancer-cell proliferation across cell lineages when PRMT5 or its binding partner WDR77 were suppressed. Mass spectrometry quantification of metabolite levels in MTAP-proficient and MTAP-deficient cells indicated that MTAP loss increased the abundance of MTA, in accordance with the first study, without affecting the levels of other metabolites, including SAM, and MTA accumulation suppressed PRMT5 histone methyltransferase activity. MTAP-deficient cells were modestly more sensitive to PRMT5 inhibition with MTA or EPZ015666 than MTAP-proficient cells. Together, the findings of both studies indicate that MTAP loss enhances the dependence of cancer cells on PRMT5, and suggest that this dependence may be exploitable with targeted therapies.

Mavrakis KJ, McDonald III ER, Schlabach MR, Billy E, Hoffman GR, deWeck A, et al. Disordered methionine metabolism in MTAP/CDKN2A deleted cancers leads to dependence on PRMT5. Science 2016 Feb 11 [Epub ahead of print].

Kryukov GV, Wilson FH, Ruth JR, Paulk J, Tsherniak A, Marlow SE, et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 2016 Feb 11 [Epub ahead of print].