MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers
Menée à l'aide de lignées cellulaires, de modèles murins, d'échantillons tumoraux de patients atteints d'un carcinome urothélial et de données portant sur des patients atteints d'un adénocarcinome pulmonaire, cette étude met en évidence une corrélation entre une déficience de la méthylthioadénosine phosphorylase dans les tumeurs présentant une perte du locus chromosomique 9p21 et une augmentation de la sensibilité des cellules cancéreuses aux antifolates
Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAPdef) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAPdef urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAPdef patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAPdef patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAPdef associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAPdef and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.