Current mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors and updated therapy strategies in human nonsmall cell lung cancer

Zhang, Kaixian; Yuan, Qianqian

doi:10.4103/0973-1482.200613

Cited by 47 publications

(34 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the majority of lung cancers are detected at a late stage of tumor development, and in these cases the opportunity for surgery is lost and non-surgical treatments are relied upon, including chemotherapy, radiotherapy and targeted therapy. In recent years, non-surgical treatment of lung cancer has been associated with characteristics of chemotherapeutic toxicity, drug resistance and insensitivity (6,7). Therefore, the development of novel anti-lung cancer drugs with high efficiency and low toxicity is essential.…”

Section: Introductionmentioning

confidence: 99%

Anticancer effects of isofraxidin against A549 human lung cancer cells via the EGFR signaling pathway

et al. 2018

View full text Add to dashboard Cite

Lung cancer is the leading cause of mortality due to tumor malignancy worldwide. In recent years, the treatment of lung cancer with chemotherapy has demonstrated notable resistance and insensitivity. Therefore, it is of great importance to investigate anti‑lung cancer drugs with high efficiency and low toxicity. In the present study, the effects of isofraxidin on lung cancer cells and the associated mechanisms were investigated. The results revealed that, in vivo and in vitro, isofraxidin exhibited marked inhibitory effects on the A549 lung cancer cell line. The results of Cell Counting kit‑8, Transwell migration and Matrigel invasion assays, and flow cytometry to determine apoptosis, revealed that isofraxidin significantly inhibited the proliferation, migration and invasion of A549 cells, and induced the cell apoptosis. Furthermore, western blot analysis demonstrated that isofraxidin treatment led to effects on the expression of apoptosis‑associated proteins, including members of the Bcl‑2 protein family, and invasion‑associated proteins, including matrix metallopeptidase (MMP)‑2 and MMP‑9, which may occur via inhibition of the expression of phosphorylated (p)‑epidermal growth factor receptor, p‑AKT and p‑extracellular signal‑regulated kinase. This regulation of protein expression may contribute to the inhibition of proliferation, migration and invasion of A549lung cancer cells by isofraxidin. In addition, despite the inhibitory effects on the A549 lung cancer cell line, the present study revealed that isofraxidin exhibited low toxicity towards BEAS‑2B normal lung epithelial cells within a certain dose range (0‑160 µM), indicating that isofraxidin may be employed for lung cancer treatment with hypotoxicity and fewer side effects. In conclusion, isofraxidin may be a novel candidate for anti‑lung cancer chemotherapy.

show abstract

Section: Introductionmentioning

confidence: 99%

Anticancer effects of isofraxidin against A549 human lung cancer cells via the EGFR signaling pathway

et al. 2018

View full text Add to dashboard Cite

show abstract

“…epithelial-mesenchymal transition, gefitinib resistance, N-acetylcysteine, NSCLC, Src phenotypes and epithelial-mesenchymal transition (EMT). [11][12][13][14] EMT is a universal phenomenon in various physiological and pathological processes. It is clear that epithelial cells display characteristics of mesenchymal cells, accompanied by upregulation of vimentin and N-cadherin, and downregulation of E-cadherin during EMT.…”

Section: Introductionmentioning

confidence: 99%

Combined treatment with N‐acetylcysteine and gefitinib overcomes drug resistance to gefitinib in NSCLC cell line

Wang

et al. 2019

Cancer Medicine

View full text Add to dashboard Cite

We aimed to explore the molecular substrate underlying EGFR‐TKI resistance and investigate the effects of N‐acetylcysteine (NAC) on reversing EGFR‐TKI resistance. In the current research, the effects of NAC in combination with gefitinib on reversing gefitinib resistance were examined using CCK‐8 assay, combination index (CI) method, matrigel invasion assay, wound‐healing assay, flow cytometry, western blot, and quantitative real‐time PCR (qRT‐PCR). CCK8 assay showed that NAC plus gefitinib combination overcame EGFR‐TKI resistance in non‐small cell lung cancer (NSCLC) cells by lowering the value of half maximal inhibitory concentration (IC50). CI calculations demonstrated a synergistic effect between the two drugs (CI < 1). Matrigel invasion assay and wound healing assay demonstrated a decrease in migration and invasion ability of PC‐9/GR cells after NAC and gefitinib treatment. Flow cytometry displayed enhanced apoptosis in the combination group. Western blot and qRT‐PCR revealed that increased E‐cadherin and decreased vimentin in the combination group. When PP2 was administered with gefitinib, the same effects were seen. Our findings suggest that NAC could restore the sensitivity of gefitinib‐resistant NSCLC cells to gefitinib via suppressing Src activation and reversing epithelial‐mesenchymal transition.

show abstract

“…However, primary or acquired resistance to EGFR-TKIs is a major obstacle to improving the prognosis of EGFR mutation-positive NSCLC patients. The mechanisms of resistance identified to date include the secondary mutation of EGFR T790M, amplification of MET, hepatocyte growth factor (HGF) overexpression, HER2 amplification or mutation, conversion to SCLC, and epithelial-mesenchymal transition (EMT) [6,7]. However, the mechanisms responsible for resistance to EGFR-TKIs are not well understood.…”

Section: Introductionmentioning

confidence: 99%

Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer

Hidayat

Mitsuishi

Takahashi

et al. 2019

Bosn J of Basic Med Sci

View full text Add to dashboard Cite

Several recent studies suggest that cancer stem cells (CSCs) are involved in intrinsic resistance to cancer treatment. Maintenance of quiescence is crucial for establishing resistance of CSCs to cancer therapeutics. F-box/WD repeat-containing protein 7 (FBXW7) is a ubiquitin ligase that regulates quiescence by targeting the c-MYC protein for ubiquitination. We previously reported that gefitinib-resistant persisters (GRPs) in EGFR-mutant non-small cell lung cancer (NSCLC) cells highly expressed octamer-binding transcription factor 4 (Oct-4) as well as the lung CSC marker CD133, and they exhibited distinctive features of the CSC phenotype. However, the role of FBXW7 in lung CSCs and their resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in NSCLC is not fully understood. In this study, we developed GRPs from the two NSCLC cell lines PC9 and HCC827, which express an EGFR exon 19 deletion mutation, by treatment with a high concentration of gefitinib. The GRPs from both PC9 and HCC827 cells expressed high levels of CD133 and FBXW7, but low levels of c-MYC. Cell cycle analysis demonstrated that the majority of GRPs existed in the G0/G1 phase. Knockdown of the FBXW7 gene significantly reduced the cell number of CD133-positive GRPs and reversed the cell population in the G0/G1-phase. We also found that FBXW7 expression in CD133positive cells was increased and c-MYC expression was decreased in gefitinib-resistant tumors of PC9 cells in mice and in 9 out of 14 tumor specimens from EGFR-mutant NSCLC patients with acquired resistance to gefitinib. These findings suggest that FBXW7 plays a pivotal role in the maintenance of quiescence in gefitinib-resistant lung CSCs in EGFR mutation-positive NSCLC.

show abstract

Current mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors and updated therapy strategies in human nonsmall cell lung cancer

Cited by 47 publications

References 2 publications

Anticancer effects of isofraxidin against A549 human lung cancer cells via the EGFR signaling pathway

Anticancer effects of isofraxidin against A549 human lung cancer cells via the EGFR signaling pathway

Combined treatment with N‐acetylcysteine and gefitinib overcomes drug resistance to gefitinib in NSCLC cell line

Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer

Contact Info

Product

Resources

About