Abstract
Abstract HER2 is a driver and clinical target in cancers afflicting women. HER2-positive (HER2+) cancers have high rates of metastasis and lower overall survival rates compared to other cancer subtypes. The goal of this study is to test the vulnerability of HER2+ cancer cells and tumors to disruption of their actin cytoskeleton using the marine macrolide toxin mycalolide B (Myc B), as these cells are highly dependent on rapid actin polymerization and remodeling for migration and invasion into new sites of tumor growth. The effects of Myc B treatment on HER2+ breast (HCC1954) and ovarian (SKOV3) cancer cell lines were profiled in assays of cell viability, motility, and invasion. Treatments of Myc B alone or in combination with Trastuzumab were also performed in HER2+ tumor xenograft assays. Myc B showed potent growth suppressive and cytotoxic effects on HER2+ cancer cells at doses in the 70-100 nM range. At sub-lethal doses, Myc B caused a rapid loss of leading edge protrusions, and sustained defects in HER2+ cancer cell motility and invasion. HER2 internalization and killing of HER2+ cancer cells by Trastuzumab-emtansine was not compromised with Myc B treatment. In a HER2+ tumor xenograft model, Myc B treatment alone, or in combination with Trastuzumab, led to significant reductions in tumor growth and metastasis. Together, these findings identify a major vulnerability in metastasis-initiating HER2+ cancer cells to the actin toxin Myc B, and provide a rationale to exploit this vulnerability with the development of new therapeutics targeting actin. Citation Format: Sarah Nersesian, Rodette Williams, Dr. Andrew Evans, Dr. John Allingham, Dr. Andrew Craig. The macrolide toxin mycalolide B disrupts actin-driven invasion and metastasis of HER2-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3161.
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