单药 TAS102（曲氟尿苷/替匹拉西）和瑞格非尼是 FDA 批准的治疗转移性结直肠癌 (mCRC) 的药物。我们之前在多重耐药转移性结直肠癌患者的临床病例报告中报道，瑞戈非尼联合氟嘧啶可以延缓疾病进展。我们假设 TAS102 和瑞戈非尼的组合可能对 CRC 和其他胃肠道 (GI) 癌症有效，并可能在未来为晚期胃肠道癌症患者提供一种治疗选择。我们在临床前研究中研究了 TAS102 与瑞戈非尼联合使用的治疗效果，该临床前研究采用细胞培养、富集癌症干细胞的菌落球测定以及体内研究。 TAS102 与瑞戈非尼联合使用，在体外对多种胃肠道癌症（包括结直肠癌和胃癌）具有协同活性，但对肝癌细胞没有协同作用。 TAS102 抑制结肠球形成，瑞戈非尼可增强这种作用。 TAS102 联合瑞戈非尼的体内抗肿瘤作用似乎是由于抗增殖作用、坏死和血管生成抑制。无论 p53、KRAS 或 BRAF 突变如何，TAS102 加瑞戈非尼都会在异种移植肿瘤中产生生长抑制作用，尽管野生型 p53 观察到更有效的肿瘤抑制作用。 Regorafenib 显着抑制 TAS102 诱导的异种移植肿瘤中的血管生成和微血管密度，并抑制 TAS102 诱导的 ERK1/2 激活，无论体内 RAS 或 BRAF 状态如何。 TAS102 加瑞戈非尼是胃肠道癌症临床前模型中的协同药物组合，其中瑞戈非尼抑制 TAS102 诱导的微血管密度和 p-ERK 增加是起作用的机制。 TAS102 加瑞戈非尼药物组合可能会在胃癌和其他胃肠道癌症中进行进一步测试。

Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. We hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo. TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo. TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.