Abstract
Cigarette smoking is one of the most significant public health issues and the most common environmental cause of preventable cancer deaths worldwide. EGFR (Epidermal Growth Factor Receptor)-targeted therapy has been used in the treatment of LC (lung cancer), mainly caused by the carcinogens in cigarette smoke, with variable success. Presence of mutations in the KRAS (Kirsten rat sarcoma viral oncogene homolog) driver oncogene may confer worse prognosis and resistance to treatment for reasons not fully understood. NQO1 (NAD(P)H:quinone oxidoreductase), also known as DT-diaphorase, is a major regulator of oxidative stress and activator of mitomycins, compounds that have been targeted in over 600 pre-clinical trials for treatment of LC. We sequenced KRAS and investigated expression of NQO1 and five clinically relevant proteins (DNMT1, DNMT3a, ERK1/2, c-MET, and survivin) in 108 patients with non-small cell lung carcinoma (NSCLC). NQO1, ERK1/2, DNMT1, and DNMT3a but not c-MET and survivin expression was significantly more frequent in patients with KRAS mutations than those without, suggesting the following: (1) oxidative stress may play an important role in the pathogenesis, worse prognosis, and resistance to treatment reported in NSCLC patients with KRAS mutations, (2) selecting patients based on their KRAS mutational status for future clinical trials may increase success rate, and (3) since oxidation of nucleotides also specifically induces transversion mutations, the high rate of KRAS transversions in lung cancer patients may partly be due to the increased oxidative stress in addition to the known carcinogens in cigarette smoke.
Highlights
Cigarette smoking, the main cause of lung cancer, has remained as one of the most significant public health issues [1,2]
52 of the 108 (48.1%) patients included in this study had mutations in KRAS
All of the mutations originated from the guanosine nucleotide
Summary
The main cause of lung cancer, has remained as one of the most significant public health issues [1,2]. Lung cancer is the most frequent cause of cancer deaths worldwide [3]. It comprises approximately 18.2% of all cancer deaths, causing nearly as many deaths as breast, prostate, and colon cancers combined [3]. KRAS is a driver oncogene encoding for a small GTPase [5]. It activates proteins such as RAF, MEK, and ERK1/2 involved in the MAPK/ERK signal transduction pathway in response to extracellular signals received by the EGFR [6], (Figure 1). Mutations in KRAS result in the loss of its GTPase activity and constitutive activation of the downstream proteins, resulting in malignant transformation [7]
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