Abstract
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.
Highlights
Triple-negative breast cancer (TNBC) is a breast cancer subtype that lacks expression of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2), with a diagnosis rate of 15–20% in breast cancer patients[1,2,3]
Elevated β-catenin, RAS, and epidermal growth factor receptor (EGFR) levels were positively correlated in TNBC patient tissues To validate the involvement of β-catenin and RAS in the tumorigenesis of TNBC, their expression levels and relationship with EGFR expression in breast cancer patient tissues were investigated by IHC analyses of Tissue microarray (TMA)
KYA1797K suppresses the cancer stem cells (CSCs) characteristics of TNBC Since the Wnt/β-catenin pathway is known to have an important role in stem cell generation and division, we investigated the effects of KYA1797K on CSCs using a 3D culture system with patient-derived cells (PDCs) established from a residual tumor after neoadjuvant chemotherapy from a TNBC26
Summary
Triple-negative breast cancer (TNBC) is a breast cancer subtype that lacks expression of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2), with a diagnosis rate of 15–20% in breast cancer patients[1,2,3]. Without these receptors, neoadjuvant chemotherapy is the standard treatment for TNBC. Many clinical trials of drugs targeting EGFR, such as cetuximab, a recombinant EGFR monoclonal antibody, did not yield successful outcomes[10,11]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have