TITLE:
Methylthioadenosine (MTA) Rescues Methylthioadenosine Phosphorylase (MTAP)-Deficient Tumors from Purine Synthesis Inhibition in Vivo via Non-Autonomous Adenine Supply
AUTHORS:
Astrid Ruefli-Brasse, Doreen Sakamoto, Jessica Orf, Minqing Rong, Jianxia Shi, Tim Carlson, Kim Quon, Alexander Kamb, Dineli Wickramasinghe
KEYWORDS:
Methylthioadenosine Phosphorylase, Purine Metabolism, L-Alanosine, Adenine Salvage
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.2 No.4,
October
12,
2011
ABSTRACT: Methylthioadenosine phosphorylase, (MTAP) is a key enzyme in the adenine and methionine salvage pathways. MTAP is encoded on human chromosome 9p21 in close proximity to the p16INK4a and p14ARF tumor suppressor genes and is frequently co-deleted with p16INK4a in many cancers. Deletion of MTAP has been reported to create a reliance of MTAP–/– tumors on de novo purine synthesis to maintain adequate pools of AMP, leading to increased sensitivity to purine synthesis inhibitors, such as L-alanosine. The ‘Achilles heel’ created by the loss of MTAP in cancer cells provides a unique therapeutic opportunity whereby MTAP–/– tumors could be selectively targeted with purine synthesis inhibitors and normal tissues could be preferentially rescued with MTAP substrates, such as MTA. We demonstrate that, in contrast to published literature, MTAP–/– cells are not more sensitive to inhibition of de novo purine synthesis than MTAP+/+ cells. Although MTA can preferentially rescue MTAP+/+ cells from purine-synthesis inhibitor toxicity in vitro, MTA protects cells of both genotypes from L-alanosine equivalently in vivo. Our data demonstrate that in vivo, adenine salvaged from plasma and adjacent tissues is sufficient to protect MTAP–/– tumors from the effects of purine synthesis inhibitors. These results suggest targeting MTAP–/– tumors with de novo purine synthesis inhibitors is unlikely to provide significant benefit over other therapeutic strategies and may explain, at least in part, the lack of efficacy of L-alanosine in clinical trials.