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

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 ?-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 ?-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 ?-catenin and RAS has potential as a therapeutic strategy for treating GC patients resistant to current standard chemotherapies.

SUBMITTER: Ryu WJ

PROVIDER: S-EPMC6521309 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Ryu Won-Ji WJ Lee Jae Eun JE Cho Yong-Hee YH Lee Gunho G Seo Mi-Kyoung MK Lee Sang-Kyu SK Hwang Jeong-Ha JH Min Do Sik DS Noh Sung Hoon SH Paik Soonmyung S Kim Sangwoo S Cheong Jae-Ho JH Choi Kang-Yell KY

Cancers 20190408 4

<b>:</b> 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 <i>RAS</i> 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-flu ...[more]

PMID: 30965636

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Project description:Recently, we have shown that coexpression of hMet and mutant-β-catenin using sleeping beauty transposon/transposase leads to hepatocellular carcinoma (HCC) in mice that corresponds to around 10% of human HCC. In the current study, we investigate whether Ras activation, which can occur downstream of Met signaling, is sufficient to cause HCC in association with mutant-β-catenin. We also tested therapeutic efficacy of targeting β-catenin in an HCC model. We show that mutant-K-Ras (G12D), which leads to Ras activation, cooperates with β-catenin mutants (S33Y, S45Y) to yield HCC in mice. Affymetrix microarray showed > 90% similarity in gene expression in mutant-K-Ras-β-catenin and Met-β-catenin HCC. K-Ras-β-catenin tumors showed up-regulation of β-catenin targets like glutamine synthetase (GS), leukocyte cell-derived chemotaxin 2, Regucalcin, and Cyclin-D1 and of K-Ras effectors, including phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, phosphorylated mammalian target of rapamycin, phosphorylated eukaryotic translation initiation factor 4E, phosphorylated 4E-binding protein 1, and p-S6 ribosomal protein. Inclusion of dominant-negative transcription factor 4 at the time of K-Ras-β-catenin injection prevented HCC and downstream β-catenin and Ras signaling. To address whether targeting β-catenin has any benefit postestablishment of HCC, we administered K-Ras-β-catenin mice with EnCore lipid nanoparticles (LNP) loaded with a Dicer substrate small interfering RNA targeting catenin beta 1 (CTNNB1; CTNNB1-LNP), scrambled sequence (Scr-LNP), or phosphate-buffered saline for multiple cycles. A significant decrease in tumor burden was evident in the CTNNB1-LNP group versus all controls, which was associated with dramatic decreases in β-catenin targets and some K-Ras effectors, leading to reduced tumor cell proliferation and viability. Intriguingly, in relatively few mice, non-GS-positive tumors, which were evident as a small subset of overall tumor burden, were not affected by β-catenin suppression.ConclusionRas activation downstream of c-Met is sufficient to induce clinically relevant HCC in cooperation with mutant β-catenin. β-catenin suppression by a clinically relevant modality is effective in treatment of β-catenin-positive, GS-positive HCCs. (Hepatology 2017;65:1581-1599).

Dataset Information

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

Publications

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

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