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Preclinical efficacy of a novel dual PI3K/mTOR inhibitor, CMG002, alone and in combination with sorafenib in hepatocellular carcinoma

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Abstract

Purpose

Sorafenib has been the only first systemic drug that improves survival of patients with advanced hepatocellular carcinoma (HCC). However, because the response rate of sorafenib is relatively low, novel therapeutic strategies are needed to improve survival in patients with HCC. This study investigated the effect of CMG002 alone and in combination with sorafenib on HCC in vitro and vivo.

Methods

The effect of a newly developed dual PI3K/mTOR inhibitor, CMG002, on the proliferation of Huh-7 and HepG2 HCC cells was investigated using the MTT assay. Western blotting was performed to assess phosphorylation of the key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. HepG2 cells were inoculated into mice, which were treated with vehicle, sorafenib, CMG002, and their combinations. Tumor cell proliferation and tumor angiogenesis were evaluated by immunohistochemical analysis of Ki-67 and CD31, respectively. Tumor cell apoptosis was detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Levels of key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways were evaluated by western blot analysis.

Results

The combination of sorafenib and CMG002 additively inhibited Huh-7 and HepG2 cell proliferation compared to single-agent treatment. Sorafenib and CMG002 as single agents differentially inhibited or activated key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. The combination of sorafenib and CMG002 inhibited all key enzymes in the two pathways. Treatment with CMG002 for 4 weeks alone and in combination with sorafenib strongly inhibited tumor growth. CMG002 inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Furthermore, these effects were enhanced when CMG002 was combined with sorafenib.

Conclusions

The combination of CMG002 and sorafenib significantly inhibited HCC cell proliferation and tumorigenesis by inhibiting the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. These findings suggest that CMG002 to be a potential novel candidate treatment for HCC.

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Abbreviations

HCC:

Hepatocellular carcinoma

PI:

Proliferation index

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling

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Funding

This research was supported by a grant of the Research Driven Hospital R&D project, funded by the CHA Bundang Medical Center (Grant Number: BDCHA R&D 2015-25), and by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2015R1D1A1A01058653). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam, 13496, Republic of Korea

    Mi Na Kim & Seong Gyu Hwang

  2. Institute for Clinical Research, CHA Bundang Medical Center, CHA University, School of Medicine, Seongnam, Republic of Korea

    Seung Min Lee

  3. CMG Pharmaceutical CO., LTD, Seongnam, Republic of Korea

    Jin Sung Kim

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  1. Mi Na Kim
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Correspondence to Mi Na Kim.

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Kim, M.N., Lee, S.M., Kim, J.S. et al. Preclinical efficacy of a novel dual PI3K/mTOR inhibitor, CMG002, alone and in combination with sorafenib in hepatocellular carcinoma. Cancer Chemother Pharmacol 84, 809–817 (2019). https://doi.org/10.1007/s00280-019-03918-y

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