Cancer Dependencies: PRMT5 and MAT2A in MTAP/p16-Deleted Cancers

Abstract

Discovery of targeted therapies that selectively exploit the genetic inactivation of specific tumor suppressors remains a major challenge. This includes the prevalent deletion of the CDKN2A/ MTAP locus, which was first reported nearly 40 years ago. The more recent advent of RNA interference and functional genomic screening technologies led to the identification of hidden collateral lethalities occurring with passenger deletions of MTAP in cancer cells. In particular, small-molecule inhibition of the type II arginine methyltransferase PRMT5 and the S-adenosylmethionine-producing enzyme MAT2A each presents a precision medicine approach for the treatment of patients whose tumors have homozygous loss of MTAP. In this review, we highlight key aspects of MTAP, PRMT5, and MAT2A biology to provide a conceptual framework for developing novel therapeutic strategies in tumors with MTAP deletion and to summarize ongoing efforts to drug PRMT5 and MAT2A. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

MTAP loss: a possible therapeutic approach for glioblastoma

“…Any therapeutic approach based on MTAP loss will be applicable to a subgroup of patients. In some rare cases associated with non-small-cell lung cancer and some other cancers MTAP loss occurred in absence of CDKN2A deletion [ 57 ]. In such cases targeting MTAP loss may be challenging.…”

Overview of Methionine Adenosyltransferase 2A (MAT2A) as an Anticancer Target: Structure, Function, and Inhibitors

“…MAT1A and MAT2A share 85% identity homology in the amino acid sequence in humans but exhibit significant differences in the kinetic properties and affinity for substrates. The K m for methionine is lowest for MAT2A (∼19 μM), followed by MATI, and is highest for MATIII. − …”

“…Since MTAP is the only enzyme known to catalyze the degradation of MTA, the loss of MTAP is thought to lead to the accumulation of MTA in cancer cells. The increase in MTA inhibits the activity of protein arginine methyltransferase 5 (PRMT5) and increases the sensitivity to further PRMT5 deletion . This indirect vulnerability extends to the upstream metabolic enzyme MAT2A as well as downstream PRMT5 cocomplex members such as RIOK1.…”

“…The increase in MTA inhibits the activity of protein arginine methyltransferase 5 (PRMT5) and increases the sensitivity to further PRMT5 deletion. 15 This indirect vulnerability extends to the upstream metabolic enzyme MAT2A as well as downstream PRMT5 cocomplex members such as RIOK1. The synthetic lethality of MAT2A and MTAP was further validated in MTAP deletion models in vitro and in vivo.…”

Targeting the methionine−methionine adenosyl transferase 2A−S-adenosyl methionine axis for cancer therapy

“…MAT1 is predominantly expressed in the liver where it regulates the differentiation of hepatocytes and bile duct epithelial cells. MAT2 is ubiquitously expressed in normal cells and cancer cells [9,10]. MAT2 contains two subunits, MAT2A and MAT2B, serving as catalytic and regulatory subunits, respectively [11].…”