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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number496
JournalCancers
Volume11
Issue number4
DOIs
Publication statusPublished - 2019 Apr

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Catenins
Stomach Neoplasms
Drug Therapy
oxaliplatin
Heterografts
Neoplasms
Organoids
Gastrointestinal Agents
Therapeutics
Leucovorin
Neoplastic Stem Cells
Paclitaxel
Fluorouracil
Colorectal Neoplasms
Survival
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Ryu, Won Ji ; Lee, Jae Eun ; Cho, Yong Hee ; Lee, Gunho ; Seo, Mi Kyoung ; Lee, Sang Kyu ; Hwang, Jeong Ha ; Min, Do Sik ; Noh, Sung Hoon ; Paik, Soonmyung ; Kim, Sangwoo ; Cheong, Jae Ho ; Choi, Kang Yell. / A therapeutic strategy for chemotherapy-resistant gastric cancer via destabilization of both β-catenin and ras. In: Cancers. 2019 ; Vol. 11, No. 4.
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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.",
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Ryu, WJ, Lee, JE, Cho, YH, Lee, G, Seo, MK, Lee, SK, Hwang, JH, Min, DS, Noh, SH, Paik, S, Kim, S, Cheong, JH & Choi, KY 2019, 'A therapeutic strategy for chemotherapy-resistant gastric cancer via destabilization of both β-catenin and ras', Cancers, vol. 11, no. 4, 496. https://doi.org/10.3390/cancers11040496

A therapeutic strategy for chemotherapy-resistant gastric cancer via destabilization of both β-catenin and ras. / Ryu, Won Ji; Lee, Jae Eun; Cho, Yong Hee; Lee, Gunho; Seo, Mi Kyoung; Lee, Sang Kyu; Hwang, Jeong Ha; Min, Do Sik; Noh, Sung Hoon; Paik, Soonmyung; Kim, Sangwoo; Cheong, Jae Ho; Choi, Kang Yell.

In: Cancers, Vol. 11, No. 4, 496, 04.2019.

Research output: Contribution to journalArticle

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T1 - A therapeutic strategy for chemotherapy-resistant gastric cancer via destabilization of both β-catenin and ras

AU - Ryu, Won Ji

AU - Lee, Jae Eun

AU - Cho, Yong Hee

AU - Lee, Gunho

AU - Seo, Mi Kyoung

AU - Lee, Sang Kyu

AU - Hwang, Jeong Ha

AU - Min, Do Sik

AU - Noh, Sung Hoon

AU - Paik, Soonmyung

AU - Kim, Sangwoo

AU - Cheong, Jae Ho

AU - Choi, Kang Yell

PY - 2019/4

Y1 - 2019/4

N2 - 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.

AB - 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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