Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan.
Cancer Sci. 2022 Dec;113(12):4207-4218. doi: 10.1111/cas.15558. Epub 2022 Sep 13.
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 G /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.
微管靶向剂（MTAs），如紫杉烷类药物，被广泛用于癌症患者的治疗。尽管 MTAs 对结直肠癌（CRC）的治疗无效，但临床前研究表明，CRC 的一部分患者，特别是那些携带 BRAF 突变的癌症患者，可能受益于这些药物。然而，两种 MTAs，埃里布林（Eri）和长春瑞滨，已显示出有限的临床疗效。在这里，我们报告胰岛素样生长因子 1 受体（IGF-1R）信号参与 Eri 耐药性。使用 CRC 细胞系，我们表明 Eri 诱导 IGF-1R 的激活和随后向核内易位。当 IGF-1R 的激活和/或核内易位被抑制时，Eri 诱导 DNA 损伤并增强 G/M 期阻滞。在使用 Eri 耐药的 SW480 细胞系的异种移植模型中，Eri 与 IGF-1R 抑制剂 linsitinib 的联合治疗比单独使用任一药物更有效地抑制肿瘤生长。因此，我们的结果表明，Eri 与 IGF-1R 抑制剂联合用药可能克服 Eri 耐药性，并为 CRC 提供治疗机会。
