Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas.
Mutations of the KRAS oncogene are predictive for resistance to treatment with antibodies against the epithelial growth factor receptor in patients with colorectal cancer. Overcoming this therapeutic dilemma could potentially be achieved by the introduction of drugs that inhibit signaling pathways that are activated by KRAS mutations. To identify comprehensively such signaling pathways, we profiled pretreatment biopsies and normal mucosa from 65 patients with locally advanced rectal cancer-30 of which carried mutated KRAS-using global gene expression microarrays. By comparing all tumor tissues exclusively to matched normal mucosa, we could improve assay sensitivity, and identified a total of 22,297 features that were differentially expressed (adjusted P-value <0.05) between normal mucosa and cancer, including several novel potential rectal cancer genes. We then used this comprehensive description of the rectal cancer transcriptome as the baseline for identifying KRAS-dependent alterations. The presence of activating KRAS mutations is significantly correlated to an upregulation of 13 genes (adjusted P-value <0.05), among them DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase. Inhibition of the expression of both genes has previously been shown using the MEK1-inhibitor PD98059 and the antibacterial compound Novobiocin, respectively. These findings suggest a potential approach to overcome resistance to treatment with antibodies against the epithelial growth factor receptor in patients with KRAS-mutant rectal carcinomas.
Gaedcke
Jochen
J
Department of General and Visceral Surgery, University Medicine, Göttingen, Germany.
Grade
Marian
M
Jung
Klaus
K
Camps
Jordi
J
Jo
Peter
P
Emons
Georg
G
Gehoff
Anastasia
A
Sax
Ulrich
U
Schirmer
Markus
M
Becker
Heinz
H
Beissbarth
Tim
T
Ried
Thomas
T
Ghadimi
B Michael
BM
D001706:Biopsy; D054637:Dual-Specificity Phosphatases / Q000235:genetics*; D020869:Gene Expression Profiling; D011905:Genes, ras; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D012004:Rectal Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics*
D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases