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Cancers 2019, 11(4), 496; https://doi.org/10.3390/cancers11040496

A Therapeutic Strategy for Chemotherapy-Resistant Gastric Cancer via Destabilization of Both β-Catenin and RAS

1
Translational Research Center for Protein Function Control, Yonsei University, Seoul 03722, Korea
2
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
3
Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea
4
Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Korea
5
Graduate Program for Nanomedical Science, Yonsei University, Seoul 03722, Korea
6
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
7
Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan 46241, Korea
8
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea
9
CK Biotechnology Inc., Rm 417, Engineering Research Park, 50 Yonsei Ro, Seodaemun-Gu, Seoul 03722, Korea
*
Authors to whom correspondence should be addressed.
Received: 29 March 2019 / Revised: 4 April 2019 / Accepted: 4 April 2019 / Published: 8 April 2019
PDF [619 KB, uploaded 8 April 2019]

Abstract

: Treatment of advanced gastric cancer patients with current standard chemotherapeutic agents frequently results in resistance, leading to poor overall survival. However, there has been no success in developing strategies to overcome it. We showed the expression levels of both β-catenin and RAS were significantly increased and correlated in tissues of 756 gastric cancer (GC) patients and tissues of primary- and acquired-resistance patient-derived xenograft tumors treated with 5-fluorouracil and oxaliplatin modulated with leucovorin (FOLFOX). On the basis of our previous studies, where small molecules to suppress colorectal cancer (CRC) via degrading both β-catenin and RAS were developed, we tested the effectiveness of KYA1797K, a representative compound functioning by binding axin, in the growth of GC cells. The efficacy test of the drugs using gastric tumor organoids of Apc1638N mice showed that the CD44 and ALDH1A3 cancer stem cell markers were induced by FOLFOX, but not by KYA1797K. KYA1797K also efficiently suppressed tumors generated by re-engrafting the FOLFOX-resistant patient-derived xenograft (PDX) tumors, which also showed resistance to paclitaxel. Overall, the small-molecule approach degrading both β-catenin and RAS has potential as a therapeutic strategy for treating GC patients resistant to current standard chemotherapies.
Keywords: gastric cancer; chemotherapy resistance; degradation of both β-catenin and RAS; gastric cancer patient-derived xenograft gastric cancer; chemotherapy resistance; degradation of both β-catenin and RAS; gastric cancer patient-derived xenograft
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Ryu, W.-J.; Lee, J.E.; Cho, Y.-H.; Lee, G.; Seo, M.-K.; Lee, S.-K.; Hwang, J.-H.; Min, D.S.; Noh, S.H.; Paik, S.; Kim, S.; Cheong, J.-H.; Choi, K.-Y. A Therapeutic Strategy for Chemotherapy-Resistant Gastric Cancer via Destabilization of Both β-Catenin and RAS. Cancers 2019, 11, 496.

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