Acetylsalicylic acid enhances antiproliferative effects of the EGFR inhibitor gefitinib in the absence of activating mutations in gastric cancer.
The epidermal growth factor receptor (EGFR) is highly expressed in gastric cancer indicating its suitability as a target for receptor tyrosine kinase (RTK) inhibitors. In the current study we explored the role of EGFR and its potential use as a therapeutic target in gastric cancer. First we analyzed 66 gastric cancer samples of Asian and Caucasian patients for the presence of EGFR mutations. No activating EGFR mutations were found and gefitinib alone was only weakly effective in gastric cancer cell lines. However, acetylsalicylic acid (ASA) significantly enhanced the inhibitory effects of gefitinib indicating synergistic action. Whole genome expression profiling indicated significant regulation of 120 genes in the case of co-administration of gefitinib and ASA (32 induced, 88 repressed) in gastric adenocarcinoma cells. Further analyses indicated that several important signalling pathways were effectively inhibited by simultaneous exposure to gefitinib and ASA. Our findings indicate that although gastric cancer does not seem to harbour mutations which render the cancer cells constitutively susceptible to gefitinib, the co-administration of ASA can strengthen RTK inhibitor activity in adenocarcinoma cells by EGFR activation. This is the first report of effective modulation of EGFR-inhibition activity in cancer.
Becker
J C
JC
Department of Medicine B, University of Münster, D-48129 Münster, Germany.
Müller-Tidow
C
C
Stolte
M
M
Fujimori
T
T
Tidow
N
N
Ilea
A M
AM
Brandts
C
C
Tickenbrock
L
L
Serve
H
H
Berdel
W E
WE
Domschke
W
W
Pohle
T
T
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001241:Aspirin / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D001241:Aspirin; D000077156:Gefitinib