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

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. The triple-negative breast cancer (TNBC), a highly aggressive form of breast cancer may be susceptible to drug therapy that targets two critical signaling pathways, one that governs cell fate and the other that controls the cell cycle. Researchers from Yonsei University in Seoul, South Korea, had previously synthesized a small-molecule called KYA1797K and found that could lower levels of the proteins, β-catenin (a master regulator of cell fate decisions) and RAS (which controls cell division), in colorectal cancer cells. Now, Kang-Yell Choi, Soonmyung Paik, and colleagues have shown that KYA1797K has the same effects on β-catenin and RAS levels in cells taken from patients with TNBC. In cell lines and mouse models, KY1797K suppressed the proliferation and metastatic capability of TNBC, highlighting the therapeutic potential of this strategy degrading both β-catenin and RAS.