Genomic-directed targeted therapy increases endometrial cancer cell sensitivity to doxorubicin.
OBJECTIVE
We aimed to utilize genome-wide expression analysis to identify molecular pathways that may contribute to endometrial cancer resistance to doxorubicin (DOX) and that also represent therapeutic targets to increase DOX sensitivity.


METHODS
Ten endometrial cancer cell lines were subjected to gene expression analysis. Sensitivity of each endometrial cell line to DOX was quantified by dimethylthiazoldiphenyltetrazoliumbromide cell proliferation assay. Pearson's correlation test was used to identify genes associated with response to DOX. Genes associated with DOX responsiveness were analyzed, and identified pathways were subjected to targeted inhibition.


RESULTS
Pearson's correlation analysis identified 2871 genes associated with DOX resistance (P < .05), which included members of the Src pathway. Targeted inhibition of the Src pathway increased DOX sensitivity in RL 95-2 (P < .0001), HEC 1B (P < .001), MEF 296 (P < .05), and MEF 280 (P = .14) cell lines.


CONCLUSIONS
Genomic analysis can identify therapeutic targets such as the Src pathway that may influence endometrial cancer DOX sensitivity.
Indermaur
Megan D
MD
Department of Women's Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33629, USA.
Xiong
Yin
Y
Kamath
Siddharth G
SG
Boren
Todd
T
Hakam
Ardeshir
A
Wenham
Robert M
RM
Apte
Sachin M
SM
Lancaster
Johnathan M
JM
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics; D004717:Endometrium / Q000166:cytology / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D052138:Genes, Neoplasm / Q000187:drug effects; D016678:Genome / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D010597:Pharmacogenetics; D011336:Probability; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012680:Sensitivity and Specificity
D000903:Antibiotics, Antineoplastic; D012313:RNA; D004317:Doxorubicin