Abstract 1698: Identification of drugs with eribulin combinatorial activity that kill both eribulin-sensitive and eribulin-insensitive tumor cells

Abstract

Abstract Eribulin mesylate, a nontaxane microtubule dynamics inhibitor with a mechanism distinct from most other antitubulin therapeutics, is clinically used in the United States for treatment of certain patients with locally advanced or metastatic breast cancer. Eribulin has broad anticancer activity in a wide variety of preclinical cancer models; as a result, numerous clinical trials are ongoing to investigate efficacy in other non-breast tumor types. We have examined eribulin sensitivity in a panel of 25 human cancer cell lines representing a variety of tumor types albeit with a preponderance of breast and lung cancer cell lines. As expected, the cell lines vary in sensitivity to eribulin at clinically relevant concentrations. To identify combination drugs capable of increasing anticancer effects in patients already responsive to eribulin, as well as inducing de novo anticancer effects in non-responders, we performed a combinatorial high throughput screen to identify drugs that combine with eribulin to selectively kill tumor cells. Among other observations, we found that inhibitors of ErbB1/ErbB2 (lapatinib, BIBW-2992, erlotinib), MEK (E6201, trametinib), PI3K (BKM-120), mTOR (AZD 8055, everolimus), and PI3K/mTOR (BEZ 235), and a BCL2 family antagonist (ABT-263) show combinatorial activity with eribulin. In addition, antagonistic pairings with other agents, such as topoisomerase I inhibitors (topotecan hydrochloride), an HSP-90 inhibitor (17-DMAG), and gemcitabine and cytarabine, were also identified. In summary, the preclinical studies described here have identified several combination drugs that have the potential to either augment or antagonize eribulin's anticancer activity. Further elucidation of the mechanisms responsible for such interactions may be important for identifying valuable therapeutic partners for eribulin. Citation Format: Toshimitsu Uenaka, Richard Rickles, Yasuhiro Funahashi, Ping Zhu, Jill M. Grenier, Janine Steiger, Nanding Zhao, Bruce A. Littlefield, Junji Matsui, Kenichi Nomoto. Identification of drugs with eribulin combinatorial activity that kill both eribulin-sensitive and eribulin-insensitive tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1698. doi:10.1158/1538-7445.AM2014-1698