Li Guoli, Liu Huan, He Jin, Li Zongwei, Wang Zhiming, Zhou Shan, Zheng Guopei, He Zhimin, Yang Jing
Cancer Research Institute and Cancer Hospital, Guangzhou Medical University Guangzhou, Guangdong, P. R. China.
Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center Houston, Texas 77030, USA.
Am J Cancer Res. 2020 Nov 1;10(11):3752-3764. eCollection 2020.
TAS-102/Lonsurf is a new oral anti-tumor drug consisting of trifluridine and tipiracil in a 1:0.5 molar ratio. Lonsurf has been approved globally, including US, Europe Union, and China, to treat patients with advanced colorectal cancer. Ongoing clinical trials are currently conducted for the treatment of other solid cancers. However, the therapeutic potential of TAS-102 in hematological malignancies has not been explored. In this study, we investigate the therapeutic efficacy of TAS-102 in multiple myeloma both and . We demonstrate that TAS-102 treatment inhibits tumor cell proliferation in six human myeloma cell lines with IC values in a range from 0.64 to 9.10 μM. Dot blotting and immunofluorescent staining show that trifluridine is predominately incorporated into genomic DNAs of myeloma cells. TAS-102 treatment induces myeloma cell apoptosis through cell cycle arrest in G1 phase and activation of cGAS-STING signaling in myeloma cells. In the human myeloma xenograft models, TAS-102 treatment reduces tumor progression and prolongs mouse survival. TAS-102 has shown its efficacies in the drug-resistant myeloma cells, and the combination of TAS-102 and bortezomib has a synergistic anti-myeloma activity. Our preclinical studies indicate that TAS-102 is a potential novel agent for myeloma therapy.
TAS-102/Lonsurf是一种新型口服抗肿瘤药物，由三氟尿苷和替匹嘧啶按1:0.5的摩尔比组成。Lonsurf已在全球范围内获批，包括美国、欧盟和中国，用于治疗晚期结直肠癌患者。目前正在进行针对其他实体癌治疗的临床试验。然而，TAS-102在血液系统恶性肿瘤中的治疗潜力尚未得到探索。在本研究中，我们研究了TAS-102在多发性骨髓瘤中的治疗效果。我们证明，TAS-102处理可抑制六种人骨髓瘤细胞系中的肿瘤细胞增殖，IC值范围为0.64至9.10μM。斑点印迹和免疫荧光染色显示，三氟尿苷主要掺入骨髓瘤细胞的基因组DNA中。TAS-102处理通过使细胞周期停滞在G1期并激活骨髓瘤细胞中的cGAS-STING信号来诱导骨髓瘤细胞凋亡。在人骨髓瘤异种移植模型中，TAS-102处理可降低肿瘤进展并延长小鼠生存期。TAS-102在耐药骨髓瘤细胞中显示出疗效，并且TAS-102与硼替佐米的联合具有协同抗骨髓瘤活性。我们的临床前研究表明，TAS-102是一种潜在的新型骨髓瘤治疗药物。
