Increased NQO1 but Not c-MET and Survivin Expression in Non-Small Cell Lung Carcinoma with KRAS Mutations

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.

Depleting Tumor-NQO1 Potentiates Anoikis and Inhibits Growth of NSCLC

“…In previous studies our laboratory, as well as other investigators, reported that NQO1 expression levels were highly elevated in lung cancer patient tumor versus associated normal lung tissue (9, 24). Elevated tumor-NQO1 levels have provided a distinct advantage for developing NQO1-directed anticancer therapeutics such as β-lapachone and deoxyniboquinone (13, 14).…”

Oncogene KRAS activates fatty acid synthase, resulting in specific ERK and lipid signatures associated with lung adenocarcinoma

“…Second, inhibition of SCD would reduce the synthesis of only desaturated FAs but not saturated ones (25,34). Third, FASN inhibition would be specific to the FA synthesis pathway, which would deplete both desaturated and saturated FA production (35,36). Cerulenin is an inhibitor of FASN (36,37) (Fig.…”

Correlation of NQO1 and Nrf2 in Female Genital Tract Cancer and Their Precancerous Lesions (Cervix, Endometrium and Ovary)

“…Such finding has led to the suggestion that NQO1 can be important in cancer chemoprevention. However, polymorphism in the NQO1 gene has been reported to be associated with an increased risk of various cancers such as breast [ 10 ], lung [ 11 ], gastric [ 24 ] and head and neck cancer [ 25 ].…”

“…NQO1 has positive cytoplasmic expression in 76%, 60% and 65% in cervical, endometrial and ovarian carcinoma respectively. Previous studies demonstrated that NQO1 immunopositivity rate ranged between 21% and 80% [ 10 , 11 , 28 ] in various tumors. We found increased NQO1 expression from normal tissue to SIL and cervical carcinoma and then from SIL to carcinoma.…”

“…It is the main activator of quinone-containing alkylating agents such as mitomycins [ 31 ]. So that, patients with KRAS mutations may utilize quinone-containing alkylating agents more efficiently due to increased NQO1 expression [ 11 ]. On the contrary, loss of NQO1 expression appeared to be candidates for adjuvant chemotherapy in patients with cholangiocarcinoma [ 32 ].…”