Yonsei Med J.  2016 Jan;57(1):50-57. 10.3349/ymj.2016.57.1.50.

Concomitance of P-gp/LRP Expression with EGFR Mutations in Exons 19 and 21 in Non-Small Cell Lung Cancers

• Wei H
• Lu W
• Li M
• Zhang Q
• Lu S

• KMID: 2466351
• DOI: http://doi.org/10.3349/ymj.2016.57.1.50

Abstract

PURPOSE
Traditional chemotherapy is the main adjuvant therapy for the treatment of non-small cell lung cancer (NSCLC). However, the emergence of multi-drug resistance (MDR) has greatly restricted the curative effect of chemotherapy. Therefore, it is necessary to find a method to treat MDR NSCLC clinically. It is worth investigating whether NSCLCs that are resistant to traditional chemotherapy can be effectively treated with tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR).
MATERIALS AND METHODS
The expression of P-glycoprotein (P-gp) and lung resistance-related protein (LRP) was detected by immunohistochemistry, and mutations in EGFR (exons 19 and 21) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (exon 2) were detected by high-resolution melting analysis (HRMA) of surgical NSCLC specimens from 127 patients who did not undergo traditional chemotherapy or radiotherapy. A Pearson chi-square test was performed to analyze the correlations between the expression of P-gp and LRP and mutations in EGFR and KRAS.
RESULTS
The expression frequencies of P-gp and LRP were significantly higher in adenocarcinomas from non-smoking patients; the expression frequency of LRP was significantly higher in cancer tissue from female patients. The frequency of EGFR mutations was significantly higher in well to moderately differentiated adenocarcinomas from non-smoking female patients. The frequency of EGFR mutations in the cancers that expressed P-gp, LRP, or both P-gp and LRP was significantly higher than that in cancers that did not express P-gp or LRP.
CONCLUSION
NSCLCs expressing P-gp/LRP bear the EGFR mutation in exon 19 or 21 easily.

Keyword

Chemotherapy; multi-drug resistance; epidermal growth factor receptor-tyrosine kinase inhibitor; non-small cell lung cancer

MeSH Terms

Aged
Aged, 80 and over
Carcinoma, Non-Small-Cell Lung/*genetics/surgery
Exons/*genetics
Female
Humans
Lung Neoplasms/*genetics/pathology/surgery
Middle Aged
Mutation
P-Glycoprotein/*genetics
Protein Kinase Inhibitors/therapeutic use
Proto-Oncogene Proteins/*genetics
Proto-Oncogene Proteins p21(ras)
Receptor, Epidermal Growth Factor/*genetics
Treatment Outcome
Vault Ribonucleoprotein Particles/*genetics
ras Proteins/*genetics
P-Glycoprotein
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Proto-Oncogene Proteins p21(ras)
Receptor, Epidermal Growth Factor
Vault Ribonucleoprotein Particles
ras Proteins

Figure

• 

  Fig. 1 High-resolution melting curves for exon 19 of the EGFR gene. (A) Temperature shift observed in the melting curves of a NSCLC sample with a mutation in exon 19 of the EGFR and a NSCLC sample with a wild-type EGFR. Each sample was analysed in triplicate. (B) Fluorescence difference curves of the same samples depicted in A. The NSCLC sample with a mutation in EGFR exon 19 is a well differentiated adenocarcinoma from a non-smoking woman. NSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor.

• 

  Fig. 2 High-resolution melting curves for exon 21 of the EGFR gene. (A) Temperature shift observed in the melting curves of a NSCLC sample with a mutation in exon 21 of the EGFR and a NSCLC sample with a wild-type EGFR. Each sample was analysed in triplicate. (B) Fluorescence difference curves of the same samples depicted in A. The NSCLC sample with a mutation in EGFR exon 21 is a moderately differentiated adenocarcinoma from a non-smoking woman. NSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor.

• 

  Fig. 3 Immunohistochemical staining of P-glycoprotein and lung resistance-related protein expression in NSCLC samples. Immunohistochemical staining of P-glycoprotein expression (A) and lung resistance-related protein expression (B) in the same sample (a well differentiated adenocarcinoma from a female non-smoker). This was the NSCLC sample with a mutation in exon 19 of the epidermal growth factor receptor, as detected by high-resolution melting analysis, shown in Fig. 1. Immunohistochemical staining of P-glycoprotein expression (C) and lung resistance-related protein expression (D) in the same sample (a moderately differentiated adenocarcinoma from a non-smoking woman). This sample was the NSCLC sample that carried a mutation in exon 21 of the epithemal growth factor receptor, as detected by high-resolution melting, shown in Fig. 2. Original magnification: ×400. NSCLC, non-small cell lung cancer.

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