MTAP Loss in NSCLC: Insights Into Synthetic Lethality

Homozygous deletion of the 9p21.3 genomic locus (9p21 loss), encompassing several genes including cyclin-dependent kinase 2A/B (CDKN2A/B) and methylthioadenosine phosphorylase (MTAP), occurs in approximately 15% of cancers1 (Fig. 1). The frequency of MTAP loss in NSCLC has been reported to be 13%,2 and low MTAP expression as assessed by immunohistochemistry (IHC) has been linked to poorer prognosis in lung adenocarcinoma.3 MTAP is a critical enzyme in the methionine salvage pathway that catalyzes the cleavage of 5′-methylthioadenosine (MTA), the by-product of polyamine synthesis, into adenine and 5-methythioribose-1-phosphate (MTR-1-P), which ultimately regenerates methionine4 (Fig.