Pancreatic cancer is a major malignant tumor without an effective treatment. KRAS mutations occur in 90% of the pancreatic cancer patients and are a major obstacle for treatment of pancreatic cancer. Pancreatic cancer patients have been treated with limited chemotherapeutic agents such as gemcitabine. However, patients often develop resistance to gemcitabine that is attributed to KRAS mutations. Gemcitabine treatment activates both the Wnt/β-catenin and RAS/ERK pathways. These signaling pathways are also activated in the gemcitabine-resistant pancreatic cancer cell lines, suggesting that they play an important role in gemcitabine resistance in pancreatic cancer. The gemcitabine-resistant cell lines show enhanced migratory and invasive capabilities than their parental lines. Therefore, we investigated the effects of a small molecule, KYA1797K that degrades both β-catenin and RAS, on pancreatic cancer. KYA1797K decreased the expression level of both β-catenin and KRAS in pancreatic cancer cell lines expressing either wild-type or mutant KRAS. It also suppressed migration and invasion of gemcitabine-resistant and parental pancreatic cancer cells. Overall, we demonstrated that inhibiting the Wnt/β-catenin and RAS/ERK pathways by destabilizing β-catenin and RAS could be a therapeutic approach to overcome gemcitabine resistance in pancreatic cancer.

01 Dec 2020·Cell Communication and SignalingQ2 · BIOLOGY

Small molecule-induced simultaneous destabilization of β-catenin and RAS is an effective molecular strategy to suppress stemness of colorectal cancer cells

Q2 · BIOLOGY

ArticleOA

Author: Cho, Jaebeom ; Kang, Dong Woo ; Lee, Ho-Young ; Cho, Yong-Hee ; Ro, Eun Ji ; Choi, Kang-Yell ; Kwak, Dong-Kyu ; Yoon, Jeong-Su

AbstractBackgroundCancer stem cells (CSCs), the major driver of tumorigenesis, is a sub-population of tumor cells responsible for poor clinical outcomes. However, molecular mechanism to identify targets for controlling CSCs is poorly understood.MethodsGene Set Enrichment Analyses (GSEA) of Wnt/β-catenin and RAS signaling pathways in stem-like subtype of colorectal cancer (CRC) patients were performed using two gene expression data set. The therapeutic effects of destabilization of β-catenin and RAS were tested by treatment of small molecule KYA1797K using CRC patient derived cells.ResultsTreatment with KYA1797K, a small molecule that destabilizes both β-catenin and RAS via Axin binding, effectively suppresses the stemness of CSCs as shown in CRC spheroids and small intestinal tumors of ApcMin/+/K-RasG12DLA2 mice. Moreover, KYA1797K also suppresses the stemness of cells in CRC patient avatar model systems, such as patient-derived tumor organoids (PDTOs) and patient-derived tumor xenograft (PDTX).ConclusionOur results suggest that destabilization of both β-catenin and RAS is a potential therapeutic strategy for controlling stemness of CRC cells.

01 May 2020·Experimental & Molecular MedicineQ2 · MEDICINE

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

Q2 · MEDICINE

ArticleOA

Author: Cho, Yong-Hee ; Cha, Pu-Hyeon ; Choi, Kang-Yell ; Sohn, Joo Hyuk ; Lee, Jeong Dong ; Paik, Soonmyung ; Park, Jong-Chan ; Kim, Jee Ye ; Ryu, Won-Ji

AbstractTriple-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.

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Preclinical	KR	Yonsei University	13 Jun 2016

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