Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies

Abstract

Lung cancer is currently the leading cause of cancer death in Western nations. Non-small cell lung cancer (NSCLC) represents 80% of all lung cancers, and adenocarcinoma is the predominant histological type. Despite the intensive research carried out on this field and therapeutic advances, the overall prognosis of these patients remains unsatisfactory, with a 5-year overall survival rate of less than 15%. Nowadays, pharmacogenetics and pharmacogenomics represent the key to successful treatment. Recent studies suggest the existence of two distinct molecular pathways in the carcinogenesis of lung adenocarcinoma: one associated with smoking and activation of the K-Ras oncogene and the other not associated with smoking and activation of the epidermal growth factor receptor (EGFR). The K-ras mutation is mainly responsible for primary resistance to new molecules which inhibit tyrosine kinase EGFR (erlotinib and gefitinib) and most of the EGFR mutations are responsible for increased tumor sensitivity to these drugs. This article aims to conduct a systematic review of the literature regarding the molecular pathways involving the EGFR, K-Ras and EGFR targeted therapies in NSCLC tumor behavior.

Mitogen-Activated Protein Kinase Signal Transduction in Solid Tumors

“…So, based on these mechanisms, K-ras mutations, EGFR (also related to phosphorylation and tyosine kinase) mutations, copy number, and expression, should be better molecular biomarkers for patient selection Hassanein et al, 2012). In clinical medicine, there are also other markers such as COX-2, p53 (de Mello et al, 2011).…”

“…In other experiments, by knocking down and over-expression of EAPII in NSCLC, C Li.et.al found that EAPII significantly affected Raf1 and ERK1/2 (important composition of the MAPK signal pathway) and during the process, the MAPK-ERK pathway which elevates levels of MYC and cyclin D1 was activated. In their hypothesis, EAPII has an oncogenic role in lung cancer development (Li et al, 2011a), As for the Ras/MAPK pathway, EGFR protein activates both K-Ras 4B and H-Ras in different ways, and affects nuclear transcription of several downstream genes in a GTP-dependent way (de Mello et al, 2011).…”

Molecular Profiling in Non–Small Cell Lung Cancer: A Step Toward Personalized Medicine

“…These intracellular signaling pathways essentially channel the signal emanating from the cell surface into the nucleus, where they modulate transcription of genes involved in key cellular functions, including cell survival (antiapoptosis), proliferation, angiogenesis, invasion, and metastasis. 5 Mutations in the gene encoding proteins involved in EGFR signaling cascade (KRAS, HER2/neu, BRAF, P13K, LKB1, and SHP2) are mutually exclusive somatic mutations, with the exception of P13K.…”

Biomarkers in Lung Cancer: Integration with Radiogenomics Data

“…Mutant EGFRs (either by exon 19 deletion or punctual mutation in exon 21 known as L858R) show an increased amount and duration of EGFR activation compared with wild-type receptors [18]. Mutated EGFR can activate RAS/RAF/MEK/MAPK and phosphoinositide 3-kinase (PI3K)/AKT and STAT3/STAT5 pathways [19][20][21]. Beside the importance of EGFR on lung carcinogenesis, some other molecules have been described as molecular markers for prognosis and therapeutic targets.…”