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A therapeutic strategy for chemotherapy-resistant gastric cancer via destabilization of both β-catenin and ras

 Won-Ji Ryu  ;  Jae Eun Lee  ;  Yong-Hee Cho  ;  Gunho Lee   ;  Mi-kyoung Seo  ;  Sang-Kyu Lee   ;  Jeong-Ha Hwang  ;  Do Sik Min  ;  Sung Hoon Noh  ;  Soonmyung Paik  ;  Sangwoo Kim  ;  Jae-Ho Cheong  ;  Kang-Yell Choi  
 CANCERS, Vol.11(4) : E496, 2019 
Journal Title
Issue Date
chemotherapy resistance ; degradation of both β-catenin and RAS ;  gastric cancer ;  gastric cancer patient-derived xenograft
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.
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1. College of Medicine (의과대학) > Dept. of Biomedical Systems Informatics (의생명시스템정보학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Sangwoo(김상우) ORCID logo https://orcid.org/0000-0001-5356-0827
Noh, Sung Hoon(노성훈) ORCID logo https://orcid.org/0000-0003-4386-6886
Paik, Soon Myung(백순명) ORCID logo https://orcid.org/0000-0001-9688-6480
Lee, Jae Eun(이재은)
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
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