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Review Article the E3 Ubiquitin Ligase NEDD4 Mediates EGFR-TKI Acquired Resistance in Non-Small Cell Lung Cancer

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Review Article the E3 Ubiquitin Ligase NEDD4 Mediates EGFR-TKI Acquired Resistance in Non-Small Cell Lung Cancer Int J Clin Exp Med 2019;12(10):12013-12019 www.ijcem.com /ISSN:1940-5901/IJCEM0097934 Review Article The E3 ubiquitin ligase NEDD4 mediates EGFR-TKI acquired resistance in non-small cell lung cancer Chunsheng Hu, Hongbo Tan International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, China Received June 3, 2019; Accepted September 2, 2019; Epub October 15, 2019; Published October 30, 2019 Abstract: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have been employed as the first- line treatment for lung adenocarcinoma patients with advanced EGFR-positive mutations, especially in patients with EGFR exon 21 L858R mutation or an exon 19 deletion. However, almost all patients inevitably develop acquired resistance to EGFR-TKI after 1 to 2 years, due to EGFR gene secondary mutations, MET gene amplification, KRAS mutation, loss of phosphatase and tensin homolog (PTEN), and other mechanisms. Therefore, the EGFR-TKI ac- quired resistance becomes a bottleneck of continuation for EGFR-TKI therapy in clinic. The neuronally expressed developmentally downregulated 4 (NEDD4), an E3 ubiquitin ligase, has been demonstrated to play an important role in the development and progression of human cancers. NEDD4 is frequently overexpressed in non-small cell lung cancer carcinomas (NSCLC) and is implicated in the regulation of ubiquitination of Ras and PTEN. NEDD4 over- expression promoted cellular transformation and induced EGFR-TKI acquired resistance in NSCLC. In this review, we will describe how NEDD4 regulates EGFR-TKI acquired resistance in NSCLC, and further discuss its mechanism, including PTEN poly-ubiquitination, Ras signaling activation, and EMT conversion. Therefore, targeting NEDD4 could be a potential therapeutic strategy for NSCLC after EGFR-TKI acquired resistance. Keywords: NEDD4, non-small cell lung cancer, ubiquitination, EGFR-TKI, resistance Introduction EGFR binds to EGF to activate the intracellular domain of tyrosine kinase and it triggers the Lung cancer is the most common malignant phosphorylation of proteins in the PI3K/AKT/ tumor with the highest morbidity and mortality mTOR, Ras/Raf/MAPK, JAK/STAT signaling pa- worldwide, and is clinical broadly classified into thways, which mediates cell survival and prolif- two pathological categories: small cell lung can- eration, migration and invasion, and is involved cer (SCLC) and non-small cell lung cancer in angiogenesis when mutated [3]. Many pub- (NSCLC). NSCLC is further subdivided into lished investigations report that EGFR is overex- squamous cell carcinoma and adenocarcino- pressed in 45 to 85% of NSCLC patients, which ma, which accounts for approximately 85% of is closely related to the percentage of poor all lung cancer. In addition, the prognosis of prognosis and resistance to radiotherapy and lung cancer is still not very satisfactory after chemotherapy. Therefore, it is an important surgery, standard chemotherapy or radiothera- molecular target for lung cancer therapy. py [1]. The 5-year overall survival rate of patients with advanced NSCLC is still low, only Epidermal growth factor receptor tyrosine ki- ranging from 10% to 15% [2]. Such disappoint- nase inhibitors (EGFR-TKI), mainly quinoline ing results drive us to pursue new therapeutic compounds, inhibit the intracellular tyrosine strategies. kinase domain of EGFR by competitively bind- ing with ATP, which leads to cell cycle arrest in Epidermal growth factor receptor (EGFR), a G1 phase and an increase in apoptosis of tumor transmembrane receptor expressed by onco- cells by blocking the pathway of cellular signal gene c-ErbB, is one of the molecular target for transduction [4]. NSCLC patients with muta- NSCLC therapy. The extracellular domain of tions of the EGFR gene involving exon 19 dele- NEDD4 mediates TKI resistance in NSCLC tion or the L858R point mutation in exon 21 are PTEN hydrolyzes the phosphatase group at D3 highly sensitive to EGFR-TKI. Clinical data show position of the PIP3, resulting in PIP2 formation that considerable improvement has been made and consequently inhibiting PI3K activation by EGFR-TKI treatment with over a 70% res- [13]. In particular, the deficiency of PTEN func- ponse and almost one-year progression-free tion in tumor cells is associated with malig- survival in patients with active mutations of nance, poor clinical outcome and resistance to EGFR gene. For this reason, EGFR-TKI was app- anticancer drugs [14-17]. roved for first-line treatment of NSCLC patients with activating mutations in the EGFR gene. The activity of PTEN is regulated by post-trans- However, most patients will inevitably develop lational modification including phosphorylation acquired resistance to EGFR-TKI with 12 mo- and ubiquitination [18, 19]. NEDD4 [20], WWP2 nths [5]. Resistance to EGFR-TKI includes vari- [21], and X-linked inhibitor of apoptosis protein ous mechanisms, such as the secondary muta- (XIAP) [22] are all reported to be ubiquityltrans- tion (T790M), amplification of c-met, RAS mu- ferase E3 ligases of PTEN. Prior study has indi- tation, loss of PTEN, and other mechanisms. cated that PTEN is found in cell nuclei, and the nuclear PTEN is essential for tumor suppres- NEDD4, a HECT E3 ubiquitin ligase, is a pro- sion. The mechanism of PTEN nuclear import is duct of the Neural Precursor Cell-Expressed mediated by its mono-ubiquitination at K13 Developmentally Downregulated gene 4 and and K289 sites [23]. In contrast, PTEN poly- exerts its biological function mainly by regula- ubiquitination mediated by NEDD4 leads to tion of protein degradation in an ubiquitination- PTEN protein degradation in cytoplasm. Thus, dependent manner. Protein ubiquitination is a PTEN ploy-ubiquitination is associated with post-transcriptional modification process, wh- tumorigenesis [20]. Interestingly, nuclear trans- ich mediates a range of cell processes includ- port of PTEN may protect PTEN form poly-ubiq- ing neuronal development, tumorigenesis and uitination through NEDD4. Therefore, NEDD4 progression. Recent studies report that NEDD4 mediates protection and degradation of PTEN is overexpressed in multiple types of solid by its mono-ubiquitination and poly-ubiquitina- tumors including NSCLC [6, 7], colorectal can- tion, respectively. cer [8], gastric carcinomas [9], breast cancer [10], and bladder cancer [11]. Amodio et al. The downregulation of PTEN protein levels is up reported that NEDD4 was overexpressed in to 70% in NSCLC tumors. This downregulation 80% of lung tumors in 103 NSCLC resections can lead to PTEN inactivation and resistance to [6]. In fact, overexpression of NEDD4 facilitates EGFR-TKI in vitro and in vivo studies as well as the tumorigenicity and progression of lung can- in NSCLC patients [24, 25]. In addition, the sur- cer. Here we review the role and regulation of vival rates of NSCLC patients with activating NEDD4 in the EGFR-TKI acquired resistance of mutation of EGFR gene and low PTEN expres- NSCLC and discuss the identification of new sion were lower than those with higher PTEN biomarkers and treatment strategies for EGFR- expression [26]. Downregulation of PTEN TKI resistance in NSCLC. through ubiquitin-mediation is considered to be the main mechanism of loss of PTEN function. NEDD4 ubiquitination regulates PTEN in Furthermore, NEDD4 is a proto-oncogenic ubiq- EGFR-TKI acquired resistance uitin ligase for PTEN, which is overexpressed in 80% of NSCLC patients and negatively regu- The PTEN gene, located on chromosome 10q lates PTEN abundance by ubiquitin-mediated 23.3, encodes a 53 kDa dual-specificity lipid degradation of PTEN [6]. Recently, some evi- and protein phosphatase [12]. The activity of dence indicates that NEDD4 regulates PTEN lipid phosphatases is intimately related to the protein levels in acquired resistance to EGFR- role of PTEN as a tumor suppressor by inhibit- TKI by activation of AKT and EGFR [7, 27]. ing phosphatidylinositol 3-kinase (PI3K)/AKT Inhibition of the PI3K/AKT signal pathway can signal pathway activation. The phosphatidylino- be an effective treatment strategy to NSCLC sitol 3,4,5-trisphosphate (PIP3) is produced with acquired resistance to EGFR-TKI due to though the phosphorylation of phosphatidylino- PTEN loss [12, 28]. It has also been observed sitol 3,4-bisphosphate (PIP2) by activation of that NEDD4 overexpression correlated with PI3K, which represents the activated status. decreased levels of PTEN protein and increased 12014 Int J Clin Exp Med 2019;12(10):12013-12019 NEDD4 mediates TKI resistance in NSCLC AKT activation in lung cancer, whereas knock- tion [34]. Recent investigation showed that Ras down of NEDD4 expression inhibited PTEN stability and activity were regulated by ubiquiti- ubiquitination and increased PTEN protein lev- nation. In particular, ubiquitination of Gly-12- els [6]. Sun et al. have demonstrated that Val mutation of K-Ras increased its ability to NEDD4-mediated PTEN downregulation plays bind the downstream effectors PI3K and Raf an important role in the resistance to erlotinib [35]. It could be beneficial that pharmaceutical in HCC827/ER cells. Knock-down of NEDD4 disruption of mono-ubiquitination of K-Ras in expression inhibited PI3K/PTEN/AKT signal treating cancers with Ras mutations. Kim et al. activation and reversed the resistance to erlo- reported that H-Ras interacted with the WD40 tinib partially [7]. Taken together, NEDD4 pro- domain of β-TrCP, which promoted H-Ras ploy- motes the acquired resistance to EGFR-TKI ubiquitination and degradation.
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