Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Nat Commun. 2022 Apr 4;13(1):1797. doi: 10.1038/s41467-022-29397-z.
Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAP) 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 MTAP urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAP patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAP 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), MTAP associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAP and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.
甲基硫腺苷磷酸化酶是腺嘌呤补救途径的必需酶，在 9p21 缺失的肿瘤中常缺乏（MTAP），并且通过针对从头嘌呤合成的抗叶酸剂使肿瘤易发生合成致死。在这里，我们报告了一项单臂 II 期临床试验（NCT02693717），该试验评估了培美曲塞在 MTAP 尿路上皮癌（UC）中的疗效，主要终点为总缓解率（ORR）。7 名入组的 MTAP 患者中有 3 名对培美曲塞有反应（ORR 为 43%）。此外，一项历史队列研究显示，4 名 MTAP 患者对培美曲塞有反应，而 10 名 MTAP 阳性患者中有 1 名有反应。使用 UC 细胞系的体外和体内临床前数据表明，通过诱导 DNA 损伤和改变核苷酸池，培美曲塞的敏感性增加。此外，MTAP 敲低可增加培美曲塞的敏感性。此外，在发表的 BATTLE2 临床研究（NCT01248247）的肺腺癌回顾性队列（N = 72）中，MTAP 与培美曲塞的反应率提高相关。我们的数据表明 MTAP 与从头嘌呤抑制之间存在合成致死相互作用，这代表了更大规模前瞻性试验的有前途的治疗策略。
