Mcdonald Iii, Earl and Mavrakis, Konstantinos (2016) Working Title: Collateral loss of MTAP in CDKN2A deleted cancers leads to increased sensitivity to PRMT5 inhibition. Science, Vol. 3 (Issue ). pp. 1208-1213. ISSN 0228-9806; 0036-8075

Abstract

Working Abstract:
The use of loss of function screens to uncover cancer specific cellular vulnerabilities has been a cornerstone of functional genomics. While this approach has robustly identified several oncogenic and lineage-specific drivers, few examples of therapeutic targets tackling the loss of key tumor suppressors have been identified. The concept of collateral vulnerability, which leverages the loss of essential genes located nearby frequently deleted tumor suppressors, relies on the identification of gene paralogs for inhibition of compensatory gene function in order to create a therapeutic index. In this study, we use a deep coverage epigenetic-focused shRNA library to interrogate functional cancer dependencies and uncover a collateral vulnerability upon loss of the 9p21 tumor suppressor locus encompassing CDKN2A and its neighboring gene MTAP. MTAP, is an enzyme in the methionine salvage pathway, that when lost results in accumulation of the metabolic byproduct MTA. Our data suggests that MTA itself creates a synthetic sensitization to loss of the protein arginine methyltransferase, PRMT5. Here we demonstrate that MTAP-deficient cell lines are preferentially sensitive to silencing of PRMT5 and these effects are reversible by introduction of an exogenous PRMT5 that retains enzymatic activity. Reconstitution of MTAP in an MTAP-deficient cell line was also able to completely rescue PRMT5 shRNA-mediated effects on viability whereas MTA, the sole catabolic substrate for MTAP, selectively inhibited PRMT5 methyltransferase activity. Consistent with this observation, addition of MTA sensitizes MTAP expressing cells to PRMT5 inhibition. Our findings demonstrate that this collateral MTAP deletion event leads to a hypomorphic PRMT5 state, potentially creating a therapeutic window for PRMT5 inhibition in CDKN2A/MTAP deficient tumors.

Item Type:	Article
Date Deposited:	12 Oct 2016 00:45
Last Modified:	12 Oct 2016 00:45
URI:	https://oak.novartis.com/id/eprint/25223