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.
Highlights
Targeted therapies that block the activity of amplified or gain-of-function mutated oncogenes have become critical components of cancer therapy (Bollag et al 2010, Hochhaus et al 2017, Shaw et al 2014, Slamon et al 2001, Zhang et al 2012), but there remains a lack of therapies that selectively exploit loss-of-function mutations or deletions in tumor suppressors
Cases have been described where methylthioadenosine phosphorylase (MTAP) loss was detected in the absence of CDKN2A deletion in primary non-small-cell lung cancer (NSCLC) samples and cell lines (Schmid et al 1998), in the recent pan-cancer studies (PCAWG Consort. 2020), MTAP loss in the absence of concordant loss of CDKN2A appears to be a rare event, suggesting that CDKN2A is the primary deletion target on the 9p21 region that is selected for in human cancers
Identifying and translating novel synthetic lethal vulnerabilities into precision medicine approaches has been greatly enabled by the implementation of functional genomic approaches and continuous progress in their development
Summary
Annu. Rev. Cancer Biol. 2021.5:371-390. Downloaded from www.annualreviews.org Access provided by 34.230.43.35 on 11/08/21. See copyright for approved use. The Annual Review of Cancer Biology is online at cancerbio.annualreviews.org https://doi.org/10.1146/annurev-cancerbio-030419033444
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
