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

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-GSK3β 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.

• Authors: Eun A Choi, Yeon-Sook Choi, Eun Ji Lee, Shree Ram Singh, Song Cheol Kim, Suhwan Chang
• Journal: Cancer letters (Cancer Lett) Vol. 465 Pg. 82-93 (Nov 28 2019) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 31404615 (Publication Type: Journal Article)
• Copyright: Published by Elsevier B.V.

Chemical References

• BX795
• Pyridones
• Pyrimidines
• Pyrimidinones
• Thiophenes
• trametinib
• MTOR protein, human
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• TOR Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, pharmacology)
• Carcinoma, Pancreatic Ductal (drug therapy, genetics)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glycogen Synthase Kinase 3 beta (genetics)
• Humans
• Inhibitory Concentration 50
• Male
• Mice
• Pancreatic Neoplasms (drug therapy, genetics)
• Pharmacogenomic Testing
• Pyridones (administration & dosage, pharmacology)
• Pyrimidines (administration & dosage, pharmacology)
• Pyrimidinones (administration & dosage, pharmacology)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (genetics)
• Thiophenes (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays