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Specific Targeting of MTAP-Deleted Tumors with a Combination of 2'-Fluoroadenine and 5'-Methylthioadenosine
Baiqing Tang1, Hyung-Ok Lee1, Serim S An1
1Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Abstract:
Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) 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 MTAP-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 MTAP 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 MTAP tumor cells, no protection takes place because adenine is not formed. Here, we examine the effects of 6TG and 2FA in combination with MTA in vitro and in vivoIn vitro, MTA protected against both 6TG and 2FA toxicity in an MTAP-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 MTAP human tumor cell lines in mouse xenograft models. Our results suggest that 2FA+MTA may be a promising combination for treating MTAP-deleted tumors.Significance: 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. Cancer Res; 78(15); 4386-95. ©2018 AACR.
Insights
Methylthioadenosine phosphorylase (MTAP) deletion is common in cancers. Combining 2-fluoroadenine (2FA) with MTAP substrate MTA shows promise for treating MTAP-deleted tumors by selectively targeting cancer cells.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in a significant proportion of human cancers.
- MTAP deletion presents a potential therapeutic vulnerability in cancer treatment.
- MTAP's role in purine metabolism is key to understanding drug resistance mechanisms.
Purpose of the Study:
- To investigate the therapeutic potential of combining purine analogues (6TG, 2FA) with the MTAP substrate (MTA) in MTAP-deleted tumors.
- To evaluate the protective effects of MTA against purine analogue toxicity in MTAP-proficient versus MTAP-deficient cells.
- To assess the efficacy and safety of the 2FA+MTA combination in preclinical cancer models.
Main Methods:
- In vitro studies assessing the IC50 of 6TG and 2FA with and without MTA in MTAP-expressing and non-expressing cells.
- In vivo studies in mice to evaluate the toxicity and protective effects of MTA combined with 2FA or 6TG.
- Xenograft mouse models using human MTAP-deleted tumor cell lines to test the efficacy of the 2FA+MTA combination.
Main Results:
- In vitro, MTA provided MTAP-dependent protection against both 6TG and 2FA toxicity.
- In vivo, MTA protected against 2FA toxicity but not 6TG toxicity.
- The 2FA+MTA combination was well-tolerated, reversed 2FA toxicity, and inhibited tumor growth in preclinical models.
Conclusions:
- The 2FA+MTA combination demonstrates selective toxicity towards MTAP-deleted tumors.
- This combination therapy offers a promising strategy for treating cancers with MTAP loss.
- Further clinical investigation of the 2FA+MTA regimen is warranted for MTAP-deleted cancers.