Comprehensive transcriptomic analysis of molecularly targeted drugs in cancer for target pathway evaluation.
Targeted therapy is a rational and promising strategy for the treatment of advanced cancer. For the development of clinical agents targeting oncogenic signaling pathways, it is important to define the specificity of compounds to the target molecular pathway. Genome-wide transcriptomic analysis is an unbiased approach to evaluate the compound mode of action, but it is still unknown whether the analysis could be widely applicable to classify molecularly targeted anticancer agents. We comprehensively obtained and analyzed 129 transcriptomic datasets of cancer cells treated with 83 anticancer drugs or related agents, covering most clinically used, molecularly targeted drugs alongside promising inhibitors of molecular cancer targets. Hierarchical clustering and principal component analysis revealed that compounds targeting similar target molecules or pathways were clustered together. These results confirmed that the gene signatures of these drugs reflected their modes of action. Of note, inhibitors of oncogenic kinase pathways formed a large unique cluster, showing that these agents affect a shared molecular pathway distinct from classical antitumor agents and other classes of agents. The gene signature analysis further classified kinome-targeting agents depending on their target signaling pathways, and we identified target pathway-selective signature gene sets. The gene expression analysis was also valuable in uncovering unexpected target pathways of some anticancer agents. These results indicate that comprehensive transcriptomic analysis with our database (http://scads.jfcr.or.jp/db/cs/) is a powerful strategy to validate and re-evaluate the target pathways of anticancer compounds.
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Tetsuo
T
Mashima
Genome Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Masaru
M
Ushijima
Genome Center, Japanese Foundation for Cancer Research, Tokyo, Japan.|Graduate School of Public Health, Teikyo University, Tokyo, Japan.
Masaaki
M
Matsuura
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Satomi
S
Tsukahara
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Kazuhiro
K
Kunimasa
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Aki
A
Furuno
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Sakae
S
Saito
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Masami
M
Kitamura
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Taeko
T
Soma-Nagae
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Hiroyuki
H
Seimiya
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Shingo
S
Dan
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Takao
T
Yamori
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Akihiro
A
Tomida
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D063990:Gene Ontology; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D059467:Transcriptome
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors
Antitumor agents; computational biology; gene expression profiling; molecular targeted therapy; protein kinase inhibitors