The effect of acquired cisplatin resistance on sensitivity to EGFR tyrosine kinase inhibitors in EGFR mutant lung cancer cells.
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are used as first-line agents for treating nonsquamous cell lung cancer with EGFR mutation, there are many patients who have to receive these drugs following platinum-based chemotherapy. This study was designed to define whether exposure to cisplatin could affect the sensitivity to EGFR TKIs because conflicting results have been presented. We established sublines that are resistant to cisplatin from EGFR wild-type cells (A549 and H460) and EGFR mutant cells (PC-9 and HCC827). The EGFR-related signals were examined by Western blotting. MTT assay and the trypan blue exclusion method were used for the in vitro study, while tumor size and the SUV of the 18FDG-PET scans were measured in animal models. The IC50 value and apoptotic fractions after exposure to EGFR TKIs, such as gefitinib, erlotinib, and BIBW 2992, were almost the same in the cisplatin-resistant sublines compared to that of the parent cells. Although the baseline PTEN expression was reduced in the resistant cells, as was indicated in a previous study, the EGFR-related signals similarly responded to the EGFR TKIs. Furthermore, the reduced tumor size and SUV of the 18FDG-PET of the implanted tumor in nude mice according to erlotinib treatment were not different between the resistant sublines and the parent cells. In conclusion, the acquired resistance to cisplatin did not affect the sensitivity to EGFR TKIs in the EGFR mutant lung cancer cells, and this should abrogate any concerns about the use of EGFR TKIs following platinum-based chemotherapy.
Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea.
Jin Kyung
JK
Rho
Yun Jung
YJ
Choi
You Ri
YR
Choi
Sun Ye
SY
Kim
Su Jin
SJ
Choi
Chang-Min
CM
Choi
Im Il
II
Na
Jae Cheol
JC
Lee
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; D002945:Cisplatin