Specific Targeting of <i>MTAP</i>-Deleted Tumors with a Combination of 2'-Fluoroadenine and 5'-Methylthioadenosine.

Abstract

Homozygous deletion of the methylthioadenosine phosphorylase (<i>MTAP)</i> gene is a frequent event in a wide variety of human cancers and is a possible molecular target for therapy. One potential therapeutic strategy to target <i>MTAP</i>-deleted tumors involves combining toxic purine analogues such as 6'-thioguanine (6TG) or 2'-fluoroadenine (2FA) with the MTAP substrate 5'-deoxy-5'-methylthioadenosine (MTA). The rationale is that excess MTA will protect normal <i>MTAP⁺</i> cells from purine analogue toxicity because MTAP catalyzes the conversion of MTA to adenine, which then inhibits the conversion of purine base analogues into nucleotides. However, in <i>MTAP^-</i> tumor cells, no protection takes place because adenine is not formed. Here, we examine the effects of 6TG and 2FA in combination with MTA <i>in vitro</i> and <i>in vivo</i><i>In vitro</i>, MTA protected against both 6TG and 2FA toxicity in an <i>MTAP</i>-dependent manner, shifting the IC₅₀ concentration by one to three orders of magnitude. However, in mice, MTA protected against toxicity from 2FA but failed to protect against 6TG. Addition of 100 mg/kg MTA to 20 mg/kg 2FA entirely reversed the toxicity of 2FA in a variety of tissues and the treatment was well tolerated by mice. The 2FA+MTA combination inhibited tumor growth of four different <i>MTAP^-</i> human tumor cell lines in mouse xenograft models. Our results suggest that 2FA+MTA may be a promising combination for treating <i>MTAP</i>-deleted tumors.<b>Significance:</b> Loss of MTAP occurs in about 15% of all human cancers; the MTAP protection strategy presented in this study could be very effective in treating these cancers. <i>Cancer Res; 78(15); 4386-95. ©2018 AACR</i>.