Abstract 5780: E6201, a novel MEK1 inhibitor, suppresses the metastatic capability of triple-negative breast cancer cells

Background: Triple-negative breast cancer (TNBC) lacks the receptor targets ER, PR, and HER2 and thus it does not respond to receptor-targeted treatments such as hormonal therapy and trastuzumab, leaving chemotherapy as the mainstay of treatment. TNBC also has higher recurrence, metastasis, and mortality rates than other receptor subtypes. The MAPK (RAS/MEK/ERK) pathway plays a crucial role in cancer cell survival, invasion, and metastasis and critically contributes to aggressive features of TNBC, as demonstrated by our novel therapeutic synergy identification screening of RNA interference. Two BRAF inhibitors (vemurafenib and dabrafenib) and two MEK inhibitors (trametinib and cobimetinib) have received U.S. Food and Drug Administration approval for treatment of melanoma, clinically validating the potential of MAPK pathway inhibition to meaningfully benefit patients with TNBC. However, the rapidly emerging resistance of TNBC to current standard treatments and disease progression remain clinical challenges for these pathway-targeted agents. E6201 is a novel MEK1 inhibitor being evaluated in phase 1 clinical trials in patients with advanced solid tumors (NCT00794781) and with melanoma metastasized to the central nervous system (NCT03332589). In the preclinical study described herein, we determined the in vitro anti-tumor efficacy and in vivo anti-metastatic efficacy of E6201 in TNBC to prepare for further development of E6201 in the clinic. Methods: The anti-tumor effects of E6201 were examined using cell proliferation and anchorage-independent colony-formation assays. To evaluate the anti-metastatic activity of E6201 in vitro and in vivo, a migration/invasion assay and an experimental/spontaneous metastasis assay were performed, respectively. Results: In vitro cell proliferation data demonstrated that E6201 inhibited growth more effectively (half maximal inhibitory concentration [IC 50 ] range: 0.05-5 µM) than did other MEK inhibitors (selumetinib, pimasertib, and trametinib). E6201 inhibited TNBC cell-colony formation in a dose-dependent manner (P = 0.0001). Also, E6201 suppressed the migration and invasion of MDA-MB-231 (IC 50 : 1 µM) and SUM149 (IC 50 : 0.25 µM) cells in a dose-dependent manner (P = 0.001). In vivo experimental and spontaneous metastasis assays demonstrated that E6201 inhibited lung metastases of the SUM149 and MDA-MB-231-LM2 cell lines (P = 0.0001). Immunohistochemical staining demonstrated that E6201 decreased the metastatic burden in the lung (P = 0.011) and decreased phosphorylated ERK expression in a dose-dependent manner. Conclusion: Taken together, these data demonstrate that E6201 is an effective inhibitor targeting the MAPK pathway in TNBC, showing anti-tumor efficacy in vitro and anti-metastatic efficacy in vivo. Our data provide a rationale for further clinical development of E6201 as MEK-targeted therapy for treatment of TNBC. Citation Format: Jangsoon Lee, Bora LIM, Kuicheon Choi, Troy Pearson, Linda Paradiso, Thomas Myers, Debu Tripathy, Naoto T. Ueno. E6201, a novel MEK1 inhibitor, suppresses the metastatic capability of triple-negative breast cancer cells [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 5780.