Destabilization of β-catenin and RAS by targeting the Wnt/β-catenin pathway as a potential treatment for triple-negative breast cancer

• Published in: Experimental & molecular medicine Vol. 52; no. 5; pp. 832 - 842
• Main Authors: Ryu, Won-Ji, Lee, Jeong Dong, Park, Jong-Chan, Cha, Pu-Hyeon, Cho, Yong-Hee, Kim, Jee Ye, Sohn, Joo Hyuk, Paik, Soonmyung, Choi, Kang-Yell
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 01.05.2020; Nature Publishing Group UK; Nature Publishing Group; 생화학분자생물학회
• Subjects: Animal models; Breast cancer; Cancer therapies; Cell culture; Cell cycle; Cell division; Cell fate; Chemotherapy; Colorectal carcinoma; Copy number; Drug therapy; Epidermal growth factor; Epidermal growth factor receptors; Gene silencing; Metabolic pathways; Metastases; Metastasis; Patients; Signal transduction; Therapeutic applications; Tumors; Wnt protein; Xenografts; β-Catenin; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-020-0440-y

Triple-negative breast cancer (TNBC) is a severe and heterogeneous disease that lacks an approved targeted therapy and has a poor clinical outcome to chemotherapy. Although the RAS-ERK signaling axis is rarely mutated in TNBC, ~50% of TNBCs show an increased copy number and overexpression of epidermal growth factor receptor (EGFR). However, EGFR-targeted therapies have offered no improvement in patient survival, underscoring the need to explore downstream targets, including RAS. We found that both β-catenin and RAS, as well as epidermal growth factor receptor (EGFR), are overexpressed and correlated with one another in tumor tissues of TNBC patients. KYA1797K, an Axin-binding small molecule reducing β-catenin and RAS expression via degradation and suppressing EGFR expression via transcriptional repression, inhibited the proliferation and the metastatic capability of stable cell lines as well as patient-derived cells (PDCs) established from TNBC patient tissues. KYA1797K also suppressed the stemness of 3D-cultured PDCs and xenografted tumors established by using residual tumors from TNBC patients and those established by the TNBC cell line. Targeting both the Wnt/β-catenin and RAS-ERK pathways via small molecules simultaneously reducing the levels of β-catenin, RAS, and EGFR could be a potential therapeutic approach for TNBC.