Saito Yoshihito David, Li Zaibo, Lustberg Maryam, Grenade Cassandra, Wesolowski Robert
Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Department of Pathology, The Ohio State University Comprehensive Cancer Center, USA.
Cancer Treat Res Commun. 2018;16:9-12. doi: 10.1016/j.ctarc.2018.04.001. Epub 2018 Apr 23.
M6620 (formerly known as VX-970) is a potent inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), a serine/threonine-specific protein kinase involved in activation of checkpoint signaling and promotion of cell cycle arrest in response to DNA damage (inhibition constant [Ki] <300 pM, IC50 of 20 nM). ATR inhibition enhances the cytotoxic effect of DNA damaging drugs and infrared radiation (IR) in many cancer cell lines and primary human tumors. M6620 is currently under investigation in early-phase clinical trials for the treatment of a number of malignancies. Below, we report a case of a patient with metastatic prostate cancer with clonal evolution to poorly differentiated large cell neuroendocrine carcinoma who developed an exceptional response to treatment with M6620 and cisplatin on a phase I trial VX12-970-001 (NCT02157792: An Open-Label, First-in-Human Study of the Safety, Tolerability, and Pharmacokinetics of VX-970 in Combination With Cytotoxic Chemotherapy) with over 20 months of non-CNS progression free survival. We will discuss the mechanism of action of M6620, rationale for enrolling the patient in this trial and hypothesize the reasons for this exceptional response.
M6620（原名VX - 970）是共济失调毛细血管扩张症和Rad3相关蛋白（ATR）的强效抑制剂，ATR是一种丝氨酸/苏氨酸特异性蛋白激酶，参与检查点信号激活以及响应DNA损伤时促进细胞周期停滞（抑制常数[Ki]<300 pM，IC50为20 nM）。抑制ATR可增强DNA损伤药物和红外辐射（IR）在许多癌细胞系和原发性人类肿瘤中的细胞毒性作用。M6620目前正在进行多项恶性肿瘤治疗的早期临床试验。以下，我们报告一例转移性前列腺癌患者，其克隆演变为低分化大细胞神经内分泌癌，在I期试验VX12 - 970 - 001（NCT02157792：VX - 970联合细胞毒性化疗的安全性、耐受性和药代动力学的开放标签、首次人体研究）中对M6620和顺铂治疗产生了异常良好的反应，无中枢神经系统进展生存期超过20个月。我们将讨论M6620的作用机制、该患者参加此试验的理论依据，并推测这种异常反应的原因。
