Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Cancer Biology & Genetics division, Queen's Cancer Research Institute, Kingston, Ontario, Canada.
Sci Rep. 2018 Nov 22;8(1):17243. doi: 10.1038/s41598-018-35284-9.
Amplification of HER2 leads to development of HER2-positive (HER2+) cancers with high rates of metastasis compared to other cancer subtypes. The goal of this study was to probe the vulnerability of HER2+ cancer cells to a filamentous actin (F-actin) severing and capping toxin. The growth and viability of human HER2+ breast cancer (HCC1954) and ovarian cancer (SKOV3) cell lines were significantly impaired upon treatment with the marine macrolide mycalolide B (Myc B) at doses above 100 nanomolar. Further testing of Myc B in combination with the antibody-drug conjugate Trastuzumab-emtansine (T-DM1) led to improved killing of SKOV3 cells compared to either treatment alone. At sub-lethal doses, treatment of HER2+ cancer cells with Myc B resulted in rapid loss of leading edge protrusions and formation of aggresomes containing F-actin and the actin regulatory protein Cortactin. This correlated with robust inhibition of HER2+ cancer cell motility and invasion with Myc B treatment. In SKOV3 tumor xenograft assays, intratumoral injections of Myc B impaired HER2+ tumor growth and metastasis, with maximal effects observed in combination with systemic delivery of Trastuzumab. Metastasis of SKOV3 cells to the lungs following tail vein injection was also reduced by Myc B. Together, these findings provide rationale for targeting F-actin in combination with existing therapies for HER2+ cancers to reduce metastasis.
HER2 的扩增导致了 HER2 阳性（HER2+）癌症的发展，与其他癌症亚型相比，其转移率较高。本研究的目的是探究丝状肌动蛋白（F-actin）切断和加帽毒素对 HER2+癌细胞的易感性。人 HER2+乳腺癌（HCC1954）和卵巢癌（SKOV3）细胞系的生长和活力在 100 纳米以上剂量的海洋大环内酯类化合物麦角固醇 B（Myc B）治疗下显著受损。进一步测试 Myc B 与抗体药物偶联物曲妥珠单抗-美坦新（T-DM1）联合应用，与单独治疗相比，导致 SKOV3 细胞的杀伤作用得到改善。在亚致死剂量下，Myc B 处理 HER2+癌细胞导致前缘突起迅速丧失，并形成含有 F-actin 和肌动蛋白调节蛋白 Cortactin 的聚集体。这与 Myc B 治疗导致 HER2+癌细胞迁移和侵袭的强烈抑制相关。在 SKOV3 肿瘤异种移植模型中，肿瘤内注射 Myc B 可损害 HER2+肿瘤的生长和转移，与系统给予曲妥珠单抗联合使用时效果最佳。尾静脉注射后 SKOV3 细胞向肺部的转移也被 Myc B 减少。总之，这些发现为针对 F-actin 与现有 HER2+癌症治疗联合使用以减少转移提供了依据。
