Microtubule targeting agents (MTAs) such as taxanes are broadly used for the treatment of patients with cancer. Although MTAs are not effective for treatment of colorectal cancer (CRC), preclinical studies suggest that a subset of patients with CRC, especially those with cancers harboring the BRAF mutation, could benefit from such agents. However, two MTAs, eribulin (Eri) and vinorelbine, have shown limited clinical efficacy. Here, we report that insulin-like growth factor 1 receptor (IGF-1R) signaling is involved in Eri resistance. Using CRC cell lines, we showed that Eri induces activation and subsequent translocation of IGF-1R to the nucleus. When the activation and/or nuclear translocation of IGF-1R was inhibited, Eri induced DNA damage and enhanced G₂/M arrest. In a xenograft model using the Eri-resistant SW480 cell line, the combination of Eri and the IGF-1R inhibitor linsitinib suppressed tumor growth more efficiently than either single agent. Thus, our results indicated that combination dosing with Eri and an IGF-1R inhibitor could overcome Eri resistance and offer a therapeutic opportunity in CRC.

中文翻译：

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抑制胰岛素样生长因子 1 受体可增强艾日布林诱导的结直肠癌 DNA 损伤

紫杉烷等微管靶向剂 (MTA) 广泛用于治疗癌症患者。尽管 MTA 对结直肠癌 (CRC) 的治疗无效，但临床前研究表明，一部分 CRC 患者，尤其是携带BRAF突变的癌症患者，可以从此类药物中获益。然而，艾日布林 (Eri) 和长春瑞滨这两种 MTA 的临床疗效有限。在这里，我们报告胰岛素样生长因子 1 受体 (IGF-1R) 信号与 Eri 抵抗有关。使用 CRC 细胞系，我们发现 Eri 诱导 IGF-1R 的激活和随后的易位至细胞核。当 IGF-1R 的激活和/或核转位被抑制时，Eri 诱导 DNA 损伤并增强 G ₂/M 逮捕。在使用 Eri 抗性 SW480 细胞系的异种移植模型中，Eri 和 IGF-1R 抑制剂 linsitinib 的组合比任何一种单一药物更有效地抑制肿瘤生长。因此，我们的结果表明，联合给药 Eri 和 IGF-1R 抑制剂可以克服 Eri 耐药性并为 CRC 提供治疗机会。