Correlation of intrinsic chemoresistance of non-small-cell lung cancer cell lines with HER-2/neu gene expression but not with ras gene mutations.
BACKGROUND
At diagnosis, most small-cell lung cancers (SCLCs) are chemosensitive, whereas non-small-cell lung cancers (NSCLCs) are usually chemoresistant. Activation of ras genes and HER-2/neu genes (also known as ERBB2) is encountered in subpopulations of NSCLC but not in SCLC and has been linked to shortened survival. Therefore, activation of these genes may be associated with intrinsic chemoresistance in NSCLC. Studies have also suggested that the multidrug-resistant phenotype expressed by the MDR1 gene (also known as PGY1) does not correlate with the in vitro chemosensitivity of NSCLC cells or with clinical response to therapy and does not explain the spectrum of cross-resistance to drugs.


OBJECTIVE
The purpose of this study was to investigate the relationships between chemoresistance and the presence of ras gene point mutations and overexpression of the HER-2/neu gene in NSCLC cell lines, which indicates gene activation.


METHODS
Using a panel of 20 NSCLC cell lines established from untreated patients, we assessed the differences in HER-2/neu messenger RNA (mRNA) expression in the cell lines with or without ras mutations. We performed in vitro drug sensitivity testing by the tetrazolium-based MTT [i.e., 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H- tetrazolium bromide] assay with doxorubicin, carmustine, cisplatin, melphalan, mitomycin, and etoposide, and we determined the differences in IC50 values (i.e., the drug concentrations required to inhibit cell growth by 50%) for the cell lines.


RESULTS
We found a statistically significant correlation between the IC50 values for all six drugs and the degree of HER-2/neu gene expression in all 20 cell lines (r = .67-.86; P < .005) as well as in the subpopulation of eight cell lines with ras mutations (r = .83-.98; P < .05). The IC50 values for doxorubicin, carmustine, cisplatin, and melphalan were not significantly different in the cell lines with or without ras mutations, but the values for mitomycin and etoposide in lines with ras mutations were slightly lower than in those without ras mutations (borderline significance, P = .031). Levels of HER-2/neu expression in cell lines with ras mutations were lower than those without ras mutations, but the difference was not statistically significant.


CONCLUSIONS
Our findings indicate that overexpression of HER-2/neu is a marker for intrinsic multidrug resistance in NSCLC cell lines.


CONCLUSIONS
If the clinical relevance of our findings is confirmed, HER-2/neu gene expression can be used as a predictor of therapeutic failure in NSCLCs. The relationships between HER-2/neu gene expression, cell proliferation, and chemoresistance in NSCLC require further investigation.
Tsai
C M
CM
Chest Department, Veterans General Hospital-Taipei, Taiwan.
Chang
K T
KT
Perng
R P
RP
Mitsudomi
T
T
Chen
M H
MH
Kadoyama
C
C
Gazdar
A F
AF
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D017354:Point Mutation; D018719:Erb-b2 Receptor Tyrosine Kinases; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009856:Oncogene Proteins, Viral; D018719:Erb-b2 Receptor Tyrosine Kinases