2. Academic Validation
  3. Anti-tumor and anti-metastasis efficacy of E6201, a MEK1 inhibitor, in preclinical models of triple-negative breast cancer

Anti-tumor and anti-metastasis efficacy of E6201, a MEK1 inhibitor, in preclinical models of triple-negative breast cancer

  • Breast Cancer Res Treat. 2019 Jun;175(2):339-351. doi: 10.1007/s10549-019-05166-3.
Jangsoon Lee 1 2,  Bora Lim 1 2,  Troy Pearson 1,  Kuicheon Choi 1,  Jon A Fuson 1,  Chandra Bartholomeusz 1 2,  Linda J Paradiso 3,  Thomas Myers 3,  Debu Tripathy 1,  Naoto T Ueno 4 5
Affiliations

Affiliations

  • 1 Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Unit 1354, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA.
  • 3 Spirita Oncology, LLC, Natick, MA, USA.
  • 4 Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. nueno@mdanderson.org.
  • 5 Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Unit 1354, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA. nueno@mdanderson.org.
PMID: 30826934 DOI: 10.1007/s10549-019-05166-3
Abstract

Purpose: Triple-negative breast Cancer (TNBC) lacks the receptor targets Estrogen Receptor, Progesterone Receptor, and human epidermal growth factor receptor 2, and thus, it does not respond to receptor-targeted treatments. TNBC has higher recurrence, metastasis, and mortality rates than Other subtypes of breast Cancer. Mounting data suggest that the MAPK (also known as RAS-RAF-MEK-ERK) pathway is an important therapeutic target in TNBC.

Methods: To evaluate anti-tumor and anti-metastasis efficacy of E6201, we used cell proliferation assay, soft agar assay, cell cycle assay, Annexin V staining assay, immunoblotting analysis, immunohistochemistry, migration assay, invasion assay, mammary fat pad xenograft, and experimental and spontaneous metastasis xenograft models. We also evaluated the anti-tumor efficacy of E6201 plus CDK4/6 inhibitor, mTOR Inhibitor, or ATR Inhibitor.

Results: E6201 inhibited TNBC cell colony formation, migration, and invasion in a dose-dependent manner. E6201 induced G1 cell cycle arrest and Apoptosis. E6201 inhibited TNBC xenograft growth and inhibited TNBC lung metastasis and improved mouse survival in experimental metastasis and spontaneous metastasis assays. Immunohistochemical staining demonstrated that E6201 decreased the metastatic burden in the lung and decreased phosphorylated ERK expression in a dose-dependent manner. Combination of E6201 with CDK4/6 inhibitor or mTOR Inhibitor enhanced E6201's in vitro anti-tumor efficacy.

Conclusion: These results indicate that E6201 exhibits anti-tumor efficacy against TNBC in vitro and anti-metastasis efficacy against TNBC in vivo. These results provide a rationale for further clinical development of E6201 as a MAPK-pathway-targeted therapy for TNBC.

Keywords

E6201; MAPK pathway; MEK inhibitor; Metastasis; Triple-negative breast cancer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15496
    MEK1 Inhibitor