A rational approach to personalized anticancer therapy: chemoinformatic analysis reveals mechanistic gene-drug associations.
OBJECTIVE
To predict the response of cells to chemotherapeutic agents based on gene expression profiles, we performed a chemoinformatic study of a set of standard anticancer agents assayed for activity against a panel of 60 human tumor-derived cell lines from the Developmental Therapeutics Program (DTP) at the National Cancer Institute (NCI).


METHODS
Mechanistically-relevant gene:drug activity associations were identified in the scientific literature. The correlations between expression levels of drug target genes and the activity of the drugs against the NCI's 60 cell line panel were calculated across and within each tumor tissue type, using published drug activity and gene expression data.


RESULTS
Compared to other mechanistically-relevant gene-drug associations, that of triciribine phosphate (TCN-P) and adenosine kinase (ADK) was exceptionally strong--overall and within tumor tissue types-across the 60 cell lines profiled for chemosensitivity (1) and gene expression (2).


CONCLUSIONS
The results suggest ADK expression may be useful for stratifying TCN-P-responsive vs. non-responsive tumors. Based on TCN-P's mechanism of action and the observed TCN-P:ADK association, we contend that catalytic drug activation provides a rational, mechanistic basis for personalizing cancer treatment based on tumor-specific differences in the expression of drug-activating enzymes.
Shedden
Kerby
K
Department of Statistics, The University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109, USA.
Townsend
Leroy B
LB
Drach
John C
JC
Rosania
Gustavo R
GR
D000073:Acenaphthenes; D000248:Adenosine Kinase / Q000096:biosynthesis / Q000235:genetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use*; D001711:Biotransformation; D002384:Catalysis; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008490:Medical Informatics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D009841:Oligonucleotides / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology
D000073:Acenaphthenes; D000970:Antineoplastic Agents; D009841:Oligonucleotides; D012265:Ribonucleotides; C014205:triciribine phosphate; D000248:Adenosine Kinase