Mavrakis, Konstantinos and Mcdonald Iii, Earl (2016) Collateral loss of MTAP in CDKN2A deleted cancers leads to selective dependence on PRMT5. Science, 351 (6278). pp. 1208-1213. ISSN 0036-80751095-9203

Abstract

CDKN2A is frequently deleted in a wide array of human cancers, the majority of which respond poorly to current standard therapies 1-3. Despite this, no therapeutic approaches that selectively target CDNK2A deleted cancers have been identified to date. MTAP is a gene that resides proximal to CDKN2A on chromosome 9p21 and as a result is frequently co-deleted in several cancer types with high unmet medical need. By screening an epigenome-targeted deep coverage shRNA library across a large panel of cell lines from the CCLE 4, we find that the collateral loss of MTAP in CDKN2A deleted tumors leads to increased sensitivity to inhibition of the arginine methyltransferase PRMT5. MTAP is an enzyme in the methionine salvage pathway, and its loss leads to the accumulation of the metabolic byproduct MTA 5-7. Surprisingly, we found that MTA selectively inhibits the catalytic activity of PRMT5 but not other histone methyltransferases. Knockout of MTAP in an MTAP-proficient cell line led to increased MTA levels and rendered them sensitive to PRMT5 depletion. Moreover, reconstitution of MTAP in an MTAP-deficient cell line fully rescued PRMT5 dependence. Collectively, these findings indicate that the collateral loss of MTAP in CDNK2A deleted cancers leads to a hypomorphic PRMT5 state, due to MTA accumulation, that is sensitized towards further PRMT5 inhibition. Intriguingly, although the catalytic activity of PRMT5 is required for this effect, a highly potent SAM-cooperative PRMT5 catalytic inhibitor failed to recapitulate the differential growth inhibition observed by RNAi or by MTA itself. These findings suggest that PRMT5 inhibitors that phenocopy MTA will be required to best exploit the hypomorphic PRMT5 state in cancers with MTAP loss, and present an attractive therapeutic strategy for the wide spectrum of CDKN2A/MTAP deficient tumors.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/26628