Usefulness of plasma HGF level for monitoring acquired resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer

Umeguchi, Hitomi; Sueoka‐Aragane, Naoko; Kobayashi, Nozomu; Nakamura, Tomomi; Sato, Akemi; Takeda, Yuji; Hayashi, Shinichiro; Sueoka, Eisaburo; Kimura, Shinya

doi:10.3892/or.2014.3560

Cited by 18 publications

(18 citation statements)

References 31 publications

(41 reference statements)

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“…In addition, the expression levels of EGFR, HER2 and HER3 were determined in primary tumors of colorectal cancer cells, and corresponded with lymph node metastases and liver metastases (42,43). The dysregulation of human EGFR pathways by the overexpression or constitutive activation promote s tumor processes, angiogenesis and metastasis in several types of human cancer (4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Previous studies have demonstrated that tetrandrine inhibits cell metastasis in 4T1 breast cancer cells (18) and CT26 colorectal cancer cells in vivo (25).…”

Section: Discussionmentioning

confidence: 99%

“…Abnormal protein activity and/or expression levels of EGFR have been correlated with the etiology of several types of human cancer, including colorectal cancer (4,5), non-small cell lung cancer (6,7), breast cancer (8,9), head and neck squamous cell carcinoma (10,11), pancreatic cancer (12) and brain cancer (13). EGFR-targeted therapy has been validated in human colorectal cancer (14), and the chemotherapeutics include pharmacological agents, including cetuximab (Erbitux), which is an EGFR inhibitor (15).…”

Section: Introductionmentioning

confidence: 99%

“…Tetrandrine is a bisbenzylisoquinoline alkaloid, which is isolated from the dried root of Stephania tetrandra of the Inhibitory effects of tetrandrine on epidermal growth factor-induced invasion and migration in HT29 human colorectal adenocarcinoma cells CHI-TING HORNG 1,2* , JAI-SING YANG 3* , JO-HUA CHIANG 4 , CHI-CHENG LU 5 , CHIU-FANG LEE 6 , NI-NA CHIANG 6 and FU-AN CHEN Menispermaceae family (18,19). Tetrandrine has been shown to have broad pharmacological actions (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

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Inhibitory effects of tetrandrine on epidermal growth factor-induced invasion and migration in HT29 human colorectal adenocarcinoma cells

Horng

Yang

Chiang³

et al. 2015

Molecular Medicine Reports

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Abstract.Tetrandrine has been shown to reduce cancer cell proliferation and to inhibit metastatic effects in multiple cancer models in vitro and in vivo. However, the effects of tetrandrine on the underlying mechanism of HT29 human colorectal adenocarcinoma cell metastasis remain to be fully elucidated. The aim of the present study was focused on tetrandrine-treated HT29 cells following epidermal growth factor (EGF) treatment, and Transwell, gelatin zymography, gene expression and immunoblotting assays were performed to investigate metastatic effects in vitro. Tetrandrine was observed to dose-dependently inhibit EGF-induced HT29 cell invasion and migration, however, no effect on cell viability occurred following exposure to tetradrine between 0.5 and 2 µM. Tetrandrine treatment inhibited the enzymatic activity of matrix metalloprotease (MMP)-2 and MMP-9 in a concentration-dependent manner. The present study also found a reduction in the mRNA expression levels of MMP-2 and MMP-9 in the tetrandrine-treated HT29 cells. Tetrandrine also suppressed the phosphorylation of EGF receptor (EGFR) and its downstream pathway, including phosphoinositide-dependent kinase 1, phosphatidylinositol 3-kinase and phosphorylated AKT, suppressing the gene expression of MMP-2 and MMP-9. Furthermore, tetrandrine triggered mitogen-activated protein kinase signaling through the suppressing the activation of phosphorylated extracellular signal-regulated protein kinase. These data suggested that targeting EGFR signaling and its downstream molecules contributed to the inhibition of EGF-induced HT29 cell metastasis caused by tetrandrine, eventually leading to a reduction in the mRNA and gelatinase activities of MMP-2 and MMP-9, respectively. IntroductionEpidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases (1), and EGFR activation by ligand binding stimulates multiple signals, including phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen-activated protein kinases (MAPKs) and nuclear factor-κB pathways, ultimately resulting in cellular proliferation, survival, angiogenesis invasion and metastasis (2,3). Abnormal protein activity and/or expression levels of EGFR have been correlated with the etiology of several types of human cancer, including colorectal cancer (4,5), non-small cell lung cancer (6,7), breast cancer (8,9), head and neck squamous cell carcinoma (10,11), pancreatic cancer (12) and brain cancer (13). EGFR-targeted therapy has been validated in human colorectal cancer (14), and the chemotherapeutics include pharmacological agents, including cetuximab (Erbitux), which is an EGFR inhibitor (15). EGFR acts to bind an EGFR-selective ligand activated by epidermal growth factor (EGF), transforming growth factor-α, amphiregulin or neuregulin, finally leading to cell proliferation, invasion and the inhibition of apoptosis (15)(16)(17).Tetrandrine is a bisbenzylisoquinoline alkaloid, which is isolated from the dried root of Stephania tetrandra of the

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibitory effects of tetrandrine on epidermal growth factor-induced invasion and migration in HT29 human colorectal adenocarcinoma cells

Horng

Yang

Chiang³

et al. 2015

Molecular Medicine Reports

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“…As the system utilizes peripheral blood, it is possible to examine T790M repeatedly. Our previous retrospective study using the MBP-QP system demonstrated that T790M was detected in 53-56% of patients who acquired resistance to EGFR-TKI (28,29). In addition, a prospective multicenter observational study was then performed to determine whether T790M detection using MBP-QP system with plasma DNA was useful for monitoring acquired resistance to EGFR-TKI, and T790M was reproducibly detected in 40% of patients whose disease became progressive (30).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, a prospective multicenter observational study was then performed to determine whether T790M detection using MBP-QP system with plasma DNA was useful for monitoring acquired resistance to EGFR-TKI, and T790M was reproducibly detected in 40% of patients whose disease became progressive (30). HGF levels in the plasma were also determined, and an elevation of HGF of ≥1.5-fold was observed in 38% of the population (29). A combination of T790M detection and HGF quantification using plasma revealed that T790M and/or elevation of HGF were detected in 69% of that population.…”

Section: Introductionmentioning

confidence: 99%

Plasma T790M and HGF as potential predictive markers for EGFR-TKI re-challenge

et al. 2017

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Abstract. Re-challenge with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) has been suggested to potentially improve survival in certain populations of patients with advanced lung cancer, but predictive markers for the success of EGFR-TKI re-challenge have not been identified. The present study analyzed 16 re-challenges with EGFR-TKI undertaken in 12 patients with lung adenocarcinoma by investigating T790M and hepatocyte growth factor (HGF) in plasma coupled with clinical characteristics. EGFR mutations in plasma DNA were detected using the wild inhibiting PCR and quenched probe system for exon 19 deletions, and T790M and L858R were detected using the mutation-biased PCR and quenched probe system. HGF levels in the plasma were measured by enzyme-linked immunosorbent assay, and the ratio of HGF levels prior to re-challenge to those prior to the previous EGFR-TKI treatment was calculated. Two re-challenges demonstrated partial response, six remained as stable disease and eight had progressive disease (PD). A total of 4 of the 5 patients with a history of T790M positivity based on plasma DNA levels had PD. A total of 7 of the 8 patients who had ≥1.5-fold elevation of HGF prior to re-challenge with EGFR-TKI suffered PD. Elevation of the HGF ratio to ≥1.5 was significantly associated with poor response to EGFR-TKI re-challenge. Having no history of T790M and an HGF ratio <1.5 was significantly associated with a positive response to EGFR-TKI re-challenge. A combination of T790M detection and HGF quantification using plasma is a potentially useful assay system for predicting the effect of EGFR-TKI re-challenge. Future prospective studies are required to confirm the predictive validity of these markers. IntroductionEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have produced dramatic anti-cancer effects in patients with non-small cell lung cancer (NSCLC) carrying EGFR activating mutations (1-3). The first generation of EGFR-TKIs, including gefitinib and elrotinib, conferred significantly prolonged progression-free survival (PFS) in these patients. The second generation of these drugs, afatinib, brought a remarkable prolongation of overall survival, up to 33 months, in particular in patients with exon 19 deletions (4). In spite of the effectiveness of EGFR-TKIs, patients eventually acquire resistance. Several treatment strategies have been evaluated in clinical trials and practice following the onset of acquired resistance. First, agents targeted at molecules contributing to acquired resistance have been considered. Based on mechanisms including the secondary EGFR mutation, T790M, MET proto-oncogene, receptor tyrosine kinase (MET) amplification, and hepatocyte growth factor (HGF) overexpression, second and third generation EGFR-TKIs and MET inhibitors have been developed (5-9). Afatinib confers a potent anti-cancer effect against lung cancer cells harboring T790M, but a phase 2b/3 randomized trial revealed that the overall response rate and PFS of patients with lung cancer ...

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