Transcriptional profiling of targets for combination therapy of lung carcinoma with paclitaxel and mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor.
A combination of paclitaxel (Taxol) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK/Erk) inhibitor represents a rational new approach to chemotherapy. We performed Affymetrix microarray analysis to understand the global effects of this combination in lung carcinoma. Genes involved in cell cycle control, apoptosis, adhesion, proliferation, invasion, and metastasis were modulated. We observed similar patterns of gene modulation in ovarian and melanoma cell lines, indicating the general applicability of these findings. Functional genomic analysis identified two genes as new targets of drug-induced tumor apoptosis. The MGSA/Gro1 gene, important in melanoma growth, was induced by paclitaxel and reduced by MEK inhibition. Blockage of paclitaxel-induced melanoma growth stimulatory activity significantly reduced melanoma growth. Additionally, the expression of topoisomerase III beta, which exhibited a clear pattern of gene reduction by a combination of the two drugs, was significantly increased (5.7-fold) in primary lung cancers but not adjacent tissues. These findings provide potential new biomarkers and gene targets for the development of improved cancer treatment.
Taxman
Debra J
DJ
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA.
MacKeigan
Jeffrey P
JP
Clements
Casey
C
Bergstralh
Daniel T
DT
Ting
Jenny P-Y
JP
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002070:Butadienes / Q000008:administration & dosage*; D054360:Chemokine CXCL1; D018925:Chemokines / Q000096:biosynthesis; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000096:biosynthesis; D003609:Dactinomycin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008545:Melanoma / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000008:administration & dosage*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage*
D002070:Butadienes; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D009570:Nitriles; C113580:U 0126; D003609:Dactinomycin; D020929:Mitogen-Activated Protein Kinase Kinases; D017239:Paclitaxel