Gene and protein expression markers of response to combined antiangiogenic and epidermal growth factor targeted therapy in renal cell carcinoma.
BACKGROUND
Metastatic renal cell carcinoma (mRCC) patients treated with anti-vascular endothelial growth factor (VEGF) therapies demonstrate promising outcomes but not all patients benefit. Factors that predict response remain to be elucidated.


METHODS
Nephrectomy material from 37 patients with mRCC receiving bevacizumab +/- erlotinib was used for protein and gene expression assessment. Protein lysates were subjected to reverse-phase protein array profiling. RNA extracts were used to carry out gene expression microarray-based profiling. Normalized protein and gene expression data were correlated with overall survival (OS) and progression-free survival (PFS) using univariate Cox hazard model and linear regression. Immunoblotting was carried out to validate the results.


RESULTS
High protein levels of AMP-activated protein kinase and low levels of cyclin B1 (CCNB1) were associated with longer OS and PFS. Further validation revealed reduced expression and activation of phosphoinositide 3-kinase (PI3K) pathway components and cell cycle factors in patients with prolonged survival after therapy. Gene expression analysis revealed up-regulation of PI3K- and cell cycle-related pathways in patients with shorter PFS.


CONCLUSIONS
The OS and PFS of bevacizumab +/- erlotinib-treated patients with renal cell carcinoma were associated with changes in expression of protein and gene expression markers related to PI3K pathway and cell cycle signaling.
Tsavachidou-Fenner
D
D
Department of Systems Biology.
Tannir
N
N
Department of Genitourinary Medical Oncology.
Tamboli
P
P
Department of Pathology.
Liu
W
W
Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, TX.
Petillo
D
D
Department of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI, USA.
Teh
B
B
Department of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI, USA.
Mills
G B
GB
Department of Systems Biology.
Jonasch
E
E
Department of Genitourinary Medical Oncology. Electronic address: ejonasch@mdanderson.org.
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors*; D020869:Gene Expression Profiling; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D004815:Epidermal Growth Factor