Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer

Abstract

KRAS mutations are one of the most common driver mutations in non-small-cell lung cancer (NSCLC) and finding druggable target molecules to inhibit oncogenic KRAS signaling is a significant challenge in NSCLC therapy. We recently identified epiregulin (EREG) as one of several putative transcriptional targets of oncogenic KRAS signaling in both KRAS-mutant NSCLC cells and immortalized bronchial epithelial cells expressing ectopic mutant KRAS. In the current study, we found that EREG is overexpressed in NSCLCs harboring KRAS, BRAF or EGFR mutations compared with NSCLCs with wild-type KRAS/BRAF/EGFR. Small interfering RNAs (siRNAs) targeting mutant KRAS, but not an siRNA targeting wild-type KRAS, significantly reduced EREG expression in KRAS-mutant and EREG-overexpressing NSCLC cell lines. In these cell lines, EREG expression was downregulated by MEK and ERK inhibitors. Importantly, EREG expression significantly correlated with KRAS expression or KRAS copy number in KRAS-mutant NSCLC cell lines. Further expression analysis using 89 NSCLC specimens showed that EREG was predominantly expressed in NSCLCs with pleural involvement, lymphatic permeation or vascular invasion and in KRAS-mutant adenocarcinomas. In addition, multivariate analysis revealed that EREG expression is an independent prognostic marker and EREG overexpression in combination with KRAS mutations was associated with an unfavorable prognosis for lung adenocarcinoma patients. In KRAS-mutant and EREG overexpressing NSCLC cells, siRNA-mediated EREG silencing inhibited anchorage-dependent and -independent growth and induced apoptosis. Our findings suggest that oncogenic KRAS-induced EREG overexpression contributes to an aggressive phenotype and could be a promising therapeutic target in oncogenic KRAS-driven NSCLC.

Inactivation of ABL kinases suppresses non–small cell lung cancer metastasis

“…Following activation, the ABL kinases often promote phosphorylation of the activating RTK and engage in bidirectional signaling that may result in decreased internalization of the receptor (41). Activation of ABL kinases in KRAS-mutant-expressing cells may also be mediated by RTK signaling, as mutant KRAS promotes expression of the EGFR ligand epiregulin, which binds to wild-type EGFR in these cells, thereby promoting autocrine cell growth and survival (42). Thus, activation of ABL kinases in lung cancer cells with EGFR or KRAS mutations can occur independently of ABL genomic alterations.…”

Gene expression analysis in the lung of the rasH2 transgenic mouse at week 4 prior to induction of malignant tumor formation by urethane and N-methylolacrylamide

“…In the mice, increased expressions of Ereg mRNA have been reported in lung tumors induced by vinyl carbamate (Alyaqoub et al, 2008) or UR (Bauer et al, 2011). Increased expression of Ereg has also been reported in lung tumors of Tg mice that express the K-ras proto-oncogene (Sunaga et al, 2013). According to one study, mutations of the endogenous c-K-ras gene may not be the principal genetic events in UR-induced lung proliferative lesions in the rasH2 Tg mice (Mori et al, 2000), although mutations in the exogenous c-Ha-ras transgene are reported to play a pivotal role in the lung carcinogenesis (Tomisawa et al, 2003).…”

Laricitrin suppresses increased benzo(a)pyrene-induced lung tumor-associated monocyte-derived dendritic cell cancer progression

“…This result may be due to H1395 cells possessing the greatest number of risk factors, as they were obtained from a female smoker with BRAF mutation (14)(15)(16)(17)(18). Comparison between each TADC-CM and mdDC-CM indicated that HCC2935-TADC-CM had the most marked effect on the proliferation, migration and invasion of cancer cells.…”

“…The present study investigated the association between certain factors and the effect of BaP on lung cancer progression. Table I shows the background of the cell lines used in the present study (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). A previous study using CD-1 mice indicated that female mice are more susceptible to the carcinogenic effects of BaP compared with males (29).…”

“…Comparison between each TADC-CM and mdDC-CM indicated that HCC2935-TADC-CM had the most marked effect on the proliferation, migration and invasion of cancer cells. The HCC2935 cell line was established from the pleural effusion cells of an adenocarcinoma patient (18)(19)(20)(21)(22). Lung cancer with malignant pleural effusion indicates terminal-stage disease (36).…”