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A pharmacogenomic analysis using L1000CDS2 identifies BX-795 as a potential anticancer drug for primary pancreatic ductal adenocarcinoma cells

  1. Author:
    Choi, Eun A
    Choi, Yeon Sook
    Lee, Eun Ji
    Singh,Shree Ram
    Kim, Song Cheol
    Chang, Suhwan

  2. Author Address

    Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea., Basic Research Laboratory, National Cancer Institute, Frederick, MD, 21702, USA. Electronic address: singhshr@mail.nih.gov., Department of Surgery, Seoul, 05505, Republic of Korea. Electronic address: drksc@amc.seoul.kr., Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea; Department of Physiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea. Electronic address: suhwan.chang@amc.seoul.kr.,
    1. Year: 2019
    2. Date: Aug 09
    3. Epub Date: 2019 08 09
  2. Journal: Cancer letters
    1. 465
    2. Pages: 82-93
  4. Type of Article: Article
  5. ISSN: 0304-3835
  1. Abstract:

    Pancreatic cancer is one of the leading causes of cancer death, mainly due to the absence of early diagnostic tool and effective therapeutic agents. To identify an effective therapeutic agent for pancreatic ductal adenocarcinoma cells (PDAC), we used 10 Gene Expression Omnibus (GEO) data sets and L1000CDS2 pharmacogenetic search tool and obtained chemical "perturvants" that were predicted to reverse the abnormal gene expression changes in PDAC. Among 20 initial candidates, we measured IC50 for six compounds and identified BX-795, PDK1/TBK1 inhibitor, as a therapeutic candidate. We found that BX-795 inhibits primary PDAC cell proliferation more effectively than normal cells. Following molecular analysis revealed that BX-795 down-regulates mTOR-GSK3ß pathway and trigger apoptosis. Moreover, we found that BX-795 suppresses primary PDAC cell migration via downregulation of Snail and Slug. Finally, efficacy test in patient-derived xenograft model of PDAC showed BX-795 can inhibit in vivo tumor growth as efficient as gemcitabine and a combination with trametinib further suppresses tumor growth. Collectively, these results demonstrate the BX-795 as an effective therapeutic candidate for PDAC treatment. Published by Elsevier B.V.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.canlet.2019.08.002
  3. PMID: 31404615
  4. View record in Web of Science®
  5. WOS: 000491685800008
  6. PII : S0304-3835(19)30425-2

Library Notes

  1. Fiscal Year: FY2018-2019
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