Antagonism between gefitinib and cisplatin in non-small cell lung cancer cells: why randomized trials failed?
BACKGROUND
Four phase III randomized trials adding epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors to standard chemotherapeutics in patients with advanced non-small cell lung cancer (NSCLC) have failed to show benefits. The mechanism of these failures was examined.


METHODS
Fifteen previously untreated NSCLC cell lines were simultaneously treated with gefitinib plus cisplatin. Three exhibited sensitizing-EGFR mutations. Three selected lines were further tested with paclitaxel/cisplatin, paclitaxel/gefitinib, and paclitaxel/cisplatin/gefitinib combinations. The tetrazolium colorimetric assay with application of the classic isobole method was used, and dose-versus-log-response curves (DRCs) were analyzed to evaluate possible resistance mechanisms.


RESULTS
Of the 15 cell lines tested, combined gefitinib/cisplatin was significantly antagonistic in 10 wild-type and three sensitizing-EGFR mutant cell lines (group mean combination index = 1.184, 95% confidence interval = 1.12-1.24, p = 0.001). The mean combination index values of paclitaxel/cisplatin/gefitinib were higher than or comparable with those of paclitaxel/cisplatin and paclitaxel/gefitinib. DRC analysis consistently showed nonsaturable passive resistance, suggesting that gefitinib at 0.001 to 0.3 μM can interfere with cisplatin cell entry (at concentrations >1-3 μM) in a dose-dependent manner and lead to antagonism. This antagonism may or may not be schedule dependent in different cell lines.


CONCLUSIONS
In most EGFR wild-type or sensitizing-mutant NSCLC cells, the concomitant gefitinib/cisplatin combination showed antagonism, likely because gefitinib interfered with cisplatin entry into the cell. The findings that three-drug combination was not better than the two-drug combinations are in accordance with the results of the randomized trials. The EGFR-tyrosine kinase inhibitor/platinum antagonism is a possible reason for the failure of those randomized trials.
Section of Thoracic Oncology, Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan. jimtsai5124@hotmail.com
Chun-Ming
CM
Tsai
Jen-Ting
JT
Chen
David J
DJ
Stewart
Chao-Hua
CH
Chiu
Chun-Liang
CL
Lai
Shih-Yin
SY
Hsiao
Yuh-Min
YM
Chen
Kuo-Ting
KT
Chang
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000188:drug therapy / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage; D017326:Clinical Trials, Phase III as Topic / Q000592:standards*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D000077156:Gefitinib; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D017211:Treatment Failure; D014407:Tumor Cells, Cultured
D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D017239:Paclitaxel; D002945:Cisplatin; D000077156:Gefitinib