Lung cancer is the leading cause of death of both men and women across the world. Overexpression and activating mutations of the epidermal growth factor receptor-1 (EGFR1) are frequently observed and associated with poor prognosis. To inhibit the function of EGFR1, multiple antibodies and small-molecule tyrosine kinase inhibitors (TKI) that target EGFR1 have been developed. Even though some patients respond to these TKI, subsequent studies reveal that this is not the case for all nonsmall cell lung cancer (NSCLC) patients. In this study, we determine whether activation and expression levels of EGFR1, ERK, AKT, STAT3, and TWIST1 are dependent on the activating mutations of EGFR1. Protein lysates and DNA have been isolated from tumor and corresponding normal tissues of 16 NSCLC patients. Genomic-DNA is used to sequence the exons 18, 19, and 21 of EGFR1, and exon 2 of k-RAS. Protein lysates were used to determine the expression or phosphorylation levels of EGFR, STAT3, ERK, AKT, and TWIST1. Our results revealed that 16 tumor samples of NSCLC patients showed no mutation in any of the indicated exons of EGFR1 and k-RAS albeit significant levels of activation or expression of the above-mentined oncogenes. In NSCLC patients, the tumor micro-environment can be as important as the activating mutations of EGFR1. TK therapy may also be considered for patients who show high levels of activation of EGFR1 even in the absence of activating mutations.
Lung cancer is the leading cause of cancer related death among both men and women worldwide [1][2][3] . There are two major groups of lung cancer based on the histological features and response to therapy; non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC is also divided to the histological subtypes, and which accounts 80% of lung cancer patients [3,4] . Despite advances in diagnosis, 5-year survival rates are approximately 15% for all cases [5] . Since EGFR (epidermal growth factor receptors) is overexpressed in more than 80% of NSCLC patients, its overexpression is correlated with poor prognosis and chemoresistance. However, only 10% of EGFR1 overexpressing patients respond to EGFR1 TKI (tyrosine kinase inhibitor) therapy implying that EGFR1 overexpression may not be the main factor responsible for NSCLC development [6,7] . Therefore, new therapeutic strategies that specifically target other molecular pathways must be considered as alternative options. In this review, we tried to summarize the most recent studies in treatment of NSLC, and made suggestions on the basis of our results and clinical studies.
Induced expression and activation of oncogenes in NSCLC (non-small cell lung cancer) in the absence of activating mutations of EGFR and k-Ras Background: Activating mutations in exon 18,19 and 21 of EGFR and changes in codons 12,13 and 61 of k-RAS are blamed for the development of NSCLC in 88% of patients. Therefore, it is suggested that the use of tyrosine kinase (TK) inhibitors, Erlotinib or Gefitinib, can be very useful to treat NSCLC patients. NSCLC patients harboring activating mutations of EGFR are very responsive to TK inhibitors; while, patients who do not have these mutations are unresponsive to these treatment. Therefore, it is recomended that before initiating therapy with these TK inhibitors, mutation status of EGFR must be determined. Methods: The protein lysates of tumor samples and DNA have been isolated from tumor and corresponding normal tissues of 16 NSCLC patients who underwent surgery. Genomic-DNA is used to sequence exons 18, 19 and 21 of EGFR1 as well as the second exon of k-RAS. Protein lysates have also been used to determine the expression or phosphorylation levels of EGFR and down-stream elements such as, STAT3, ERK and AKT. The expression levels of metastatic factors TWIST1 and GAPDH have also been determined. Results: Even though sequence analysis of indicated regions of EGFR and k-RAS reveal no mutation, the protein analysis of 16 tumor samples show remarkable changes in the activation or expression levels of above mentioned oncogenes. Among the patients different levels of induced phosphorylation have been found; these levels are, 2 to 23 fold induced phosphorylation of ERK, 1.5 to 20 in AKT, 2 to 10 in EGFR, and 2 to 24 in TWIST1 and 2-450 in GAPDH. These results indicate that even in the absence of any activating mutations of EGFR or k-Ras, the EGFR pathway is still very active in some NSCLC patients. Conclusion: If activating mutations of EGFR is considered the main reason for TK therapy, then TK use may not be the optimal decision to make. Results clearly indicate that NSCLC patients who do not show any activating mutations of EGFR may benefit from TK therapy. Even though, activating mutations of EGFR is the “gold standard” for TK therapy, surgery materials of NSCLC patients must be examined for oncogene activation. This is especially true for the EGFR pathway since, as shown in this work, the tumor micro-environment created by the tumor or surrounding cells can be as important as the activating mutations of EGFR. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-142. doi:1538-7445.AM2012-LB-142
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