Anti‐tumor activity of <scp>WK</scp>88‐1, a novel geldanamycin derivative, in gefitinib‐resistant non‐small cell lung cancers with Met amplification

Jang, Won‐Jun; Jung, Sung-Keun; Kang, Jong Soon; Jeong, Joo‐Won; Bae, Moon‐Kyoung; Joo, Sang Hoon; Park, Gyu Hwan; Kundu, Joydeb Kumar; Hong, Young-Shick; Jeong, Chul‐Ho

doi:10.1111/cas.12497

Cited by 21 publications

(13 citation statements)

References 46 publications

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“…Recently, many strategies to overcome EGFR-TKI resistance have been developed in vitro and in vivo, and several agents are undergoing clinical trials (10). Among these agents, HSP90 inhibitors have shown favorable results for sensitization to EGFR-TKIs in NSCLC; the effects of these drugs are mediated by downregulation of HSP90 client proteins including EGFR, MET, Akt, and ErbB3 (35,36). Previously, we demonstrated that ANT2 shRNA downregulated HER2 expression in breast cancer cells, thereby exerting an antitumor effect.…”

Section: Ant2 Expression In Tumor Tissuesmentioning

confidence: 99%

Targeting Adenine Nucleotide Translocase-2 (ANT2) to Overcome Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Non–Small Cell Lung Cancer

Jang

Kim

Nam

et al. 2016

Molecular Cancer Therapeutics

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EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy has achieved favorable clinical outcomes in non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, patients eventually develop resistance to EGFR-TKIs by several mechanisms. Adenine nucleotide translocase-2 (ANT2) is an oncogenic mitochondrial membrane-associated protein. We investigated the therapeutic potential of ANT2 inhibition to EGFR-TKI resistance in NSCLC using gefitinib-sensitive (PC9 and HCC827) and gefitinib-resistant (H1975 and HCC827/ GR) NSCLC cell lines. ANT2 was inhibited by transfecting cells with an ANT2-specific shRNA. ANT2 expression was elevated in the H1975 and HCC827/GR cells compared with the PC9 and HCC827 cells. ANT2 upregulation in gefitinib-resistant cells was associated with increased SP1 binding to the ANT2 promoter. ANT2-specific shRNA decreased NSCLC cell viability.Moreover, ANT2-specific shRNA sensitized the H1975 and HCC827/GR cells to gefitinib, accompanied by HSP90 and EGFR downregulation. ANT2-specific shRNA also inactivated the PI3K/Akt signaling pathway in the H1975 and HCC827/GR cells, which was mediated by the suppression of miR-221/222 levels and by the subsequent restoration of PTEN. In EGFR-TKI-treated NSCLC patients, ANT2 expression was higher in patients exhibiting poor responses compared with patients showing excellent responses. Furthermore, ANT2 expression increased in tumor tissues biopsied after acquiring gefitinib resistance compared with tissues before gefitinib treatment. These findings suggest that ANT2 overexpression contributes to EGFR-TKI resistance in NSCLC and that ANT2 targeting may be considered a novel strategy for overcoming this resistance.

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Section: Ant2 Expression In Tumor Tissuesmentioning

confidence: 99%

Targeting Adenine Nucleotide Translocase-2 (ANT2) to Overcome Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Non–Small Cell Lung Cancer

Jang

Kim

Nam

et al. 2016

Molecular Cancer Therapeutics

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“…This result is consistent with the results of previous research. Furthermore, previous research demonstrated that Met amplification is the primary mechanism used for forming HCC827-GR cells through chronic exposure to gefitinib (38)(39)(40). In future studies, the regulation of the HIF-1 pathway on Met levels in HCC827-GR cells should be observed, and the synergistic effect of YC-1 and gefitinib in HCC827-GR cells should be demonstrated.…”

Section: Discussionmentioning

confidence: 84%

Hypoxia‑inducible factor-1 signaling pathway influences the sensitivity of HCC827 cells to gefitinib

Jin

Zhou

et al. 2019

Oncol Lett

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The majority of patients with non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations inevitably progress in stage despite an initial substantial and rapid response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Previous research indicates that hypoxia may be associated with resistance to EGFR-TKIs in EGFR mutation-positive NSCLC. Therefore, the present study regulated the activity of hypoxia-inducible factor-1 (HIF-1) signaling pathway to observe if it is able to alter the sensitivity of lung cancer cells to gefitinib. The present study selected 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) and dimethyloxalylglycine (DMOG) as a HIF-1 signaling pathway inhibitor and activator, respectively, on HCC827 cells. Cells were incubated with different treatments for different durations: A blank control, DMOG, gefitinib, or DMOG and gefitinib combined, for 36 and 48 h; and then a blank control, YC-1, gefitinib, or YC-1 and gefitinib combined, for 16 and 28 h. A western blot analysis assay was performed to evaluate the protein expression levels of HIF-1α and phosphorylated hepatocyte growth factor receptor (p-MET), an MTT assay was used to determine cell proliferation, a colony formation assay was used to investigate the colony-forming ability and a wound healing assay was used to test the cell migration ability. Additionally, Pearson's correlation analysis was used to evaluate the correlation between p-Met and HIF-1α expression levels. Finally, it was identified that gefitinib and DMOG combined notably improve the growth and cell migration ability of HCC827 cells, compared with gefitinib alone. When gefitinib and YC-1 were combined, the inhibiting effect on the growth and cell migration ability of HCC827 cells was substantially enhanced, compared with the control cells. Pearson's correlation analysis revealed that the p-Met expression level had a strong positive correlation with HIF-1α expression levels. Thus, it was concluded that the HIF-1 signaling pathway influences the sensitivity of HCC827 cells to gefitinib. The positive correlation between p-Met and HIF-1α expression levels may be the underlying mechanism of the HIF-1 signaling pathway influencing the sensitivity of HCC827 cells to gefitinib.

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“…Auy922 inhibits growth of EGFR-TKI resistant cell lines by inducing cell programmed death (63) and also displays activity against the gefitinib-resistant sublines with T790M mutation and Met amplification (102). WK88-1 reverses gefitinib resistance by interfering the EGFR or c-Met stability and functions (65). 17-AAG represents a better efficacy for treating nSClC with acquired resistance to EGFR TKIs (103) and the combination of gefitinib and 17-AAG increases nSClC cell growth inhibition (73).…”

Section: Hsp90 and Drug Resistance Of Molecular Targeted Therapymentioning

confidence: 99%

“…Furthermore, Auy922 results in obvious exhaustion of EGFR, Met, HER2 and AKT in nSClC cell lines, giving rise to a reinforcement of apoptosis(64). Hsp90 inhibitor WK88-1 reduces the cell survival of lung cancer cells via reducing the expression of EGFR, ErbB2, ErbB3, Met and Akt(65), and combination treatment of Hsp90 inhibitor ganetespib and erlotinib stabilizes the expression state of EGFR inactivation and disrupts ERK and AKT signaling activity(66). Hsp90 inhibitor 17-DMAG inhibits the growth of Ma-1/HGF cells, H1975 cells and PC-9 cells by downregulating EGFR and Met(67) and exhausting EGFR, AKT, MAPK, Cdk4, and cyclin D1 in EGFR-mutant cell lines(68).…”

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confidence: 99%

Molecular mechanism and targeted therapy of Hsp90 involved in lung cancer: New discoveries and developments (Review)

Biaoxue

Yang

2017

Int J Oncol

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The exploration of the molecular mechanisms and signaling pathways on lung cancer is very important for developing new strategies of diagnosis and treatment to this disease, such as finding valuable lung cancer markers and molecularly targeted therapies. Previously, a number of studies disclose that heat shock protein 90 (Hsp90) is upregulated in cancer cells, tissues and serum of lung cancer patients, and its upregulation intimately correlates with the occurrence, development and outcome of lung cancer. On the contrary, inhibition of Hsp90 can suppress cell proliferation, motility and metastasis of lung cancer and promote apoptosis of lung cancer cells via complex signaling pathways. In addition, a series of Hsp90 inhibitors have been investigated as effective molecular targeted therapy tactics fighting against lung cancer. This review, systematically summarizes the role of Hsp90 in lung cancer, the molecular mechanisms and development of anti-Hsp90 treatment in lung cancer.

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Anti‐tumor activity of WK88‐1, a novel geldanamycin derivative, in gefitinib‐resistant non‐small cell lung cancers with Met amplification

Cited by 21 publications

References 46 publications

Targeting Adenine Nucleotide Translocase-2 (ANT2) to Overcome Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Non–Small Cell Lung Cancer

Targeting Adenine Nucleotide Translocase-2 (ANT2) to Overcome Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Non–Small Cell Lung Cancer

Hypoxia‑inducible factor-1 signaling pathway influences the sensitivity of HCC827 cells to gefitinib

Molecular mechanism and targeted therapy of Hsp90 involved in lung cancer: New discoveries and developments (Review)

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