Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

Jin, Hyeon Ok; Hong, Sung Eun; Kim, Chang Soon; Park, Jin Ah; Kim, Jin Hee; Kim, Ji Young; Kim, Bora; Chang, Yoon Hwan; Hong, Seok Il; Hong, Young Jun; Park, In-Cheol; Lee, Jin Kyung

doi:10.1016/j.taap.2015.05.001

Cited by 7 publications

(3 citation statements)

References 35 publications

(47 reference statements)

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“…Our previous study also showed that LMB IC50 of A549 at 48 hrs (13.1 nM, p53 wide type) was much higher compared to the other two NSCLC cell lines H522 (5.7 nM, p53-mutant) and H358 (0.5 nM, p53 null) (Shao et al , 2011). It has also been reported that the mutational activation of KRAS contributes to the primary resistance of gefitinib in A549 (Pao et al , 2005b; Chen et al , 2013), and the synergistic effect of gefitinib in combined with other anticancer drugs including vATPase inhibitors (Jin et al , 2015), atorvastatin, aromatase inhibitor anastrozole, MEK inhibitor AZD6244, and cyclooxygenase-2 (COX-2) inhibitor celecoxib on overcoming the primary resistance of A549 (Shen et al , 2012; Chen et al , 2013; Li et al , 2015a; Li et al , 2015b). Our previous study found that the cytotoxic effects of cisplatin were significantly enhanced when used in combination with LMB in both in vitro A549 cells and in vivo mouse xenograft model (Gao et al , 2015).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, combinative therapeutics, such as vATPase inhibitor or celecoxib (Jin et al , 2015; Li et al , 2015a), enhanced the cytotoxic sensitivity of A549 to gefitinib by modulating signaling pathways other than EGFR such as HIF-1α and cyclooxygenase-2. Therefore, the synergistic mechanism of LMB and gefitinib observed in the present study is a novel finding in comparison with the previously reported combinative therapeutics with gefitinib in A549, featured by enhanced p-Akt, p-Erk1/2, and p21 resulting from CRM1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

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Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

Liu

Gao

2017

Toxicology and Applied Pharmacology

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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) gefitinib has demonstrated dramatic clinical efficacy in non-small cell lung cancer (NSCLC) patients. However, its therapeutic efficacy is ultimately limited by the development of acquired drug resistance. The aim of this study was to explore the potential utility of chromosome region maintenance 1 (CRM1) inhibitor leptomycin B (LMB) in combination with gefitinib to overcome primary and acquired gefitinib resistance in NSCLC cells. The combinative effects of gefitinib and LMB were evaluated by MTT and its underlining mechanism was assessed by flow cytometry and Western blot. LMB displayed a synergistic effect on gefitinib- induced cytotoxicity in A549 (IC50: 25.0±2.1 μM of gefitinib+LMB vs. 32.0±2.5 μM of gefitinib alone, p<0.05). Gefitinib+LMB caused a significantly different cell cycle distribution and signaling pathways involving in EGFR/survivin/p21 compared with gefitinib. A549 cells then were treated with progressively increasing concentrations of gefitinib (A549GR) or in combination with LMB (A549GLR) over 10 months to generate gefitinib resistance. IC50 of gefitinib in A549GLR (37.0±2.8 μM) was significantly lower than that in A549GR (53.0±3.0 μM, p<0.05), which indicates that LMB could reverse gefitinib-induced resistance in A549. Further mechanism investigation revealed that the expression patterns of EGFR pathway and epithelial- mesenchymal transition (EMT) markers in A549, A549GR, and A549GLR were significantly different. In conclusion, LMB at a very low concentration combined with gefitinib showed synergistic therapeutic effects and ameliorated the development of gefitinib- induced resistance in lung cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

Liu

Gao

2017

Toxicology and Applied Pharmacology

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“…SB02024, a novel selective inhibitor of VPS34, can enhance the cytotoxic effect of erlotinib on breast cancer cells [140]. Bafilomycin A1, an inhibitor of vacuolar adenylpyrophosphatase (vATPase), can enhance the effects of EGFR-TKIs on NSCLC cells [141]. Cepharanthine, a novel autophagy inhibitor, can enhance the sensitivity of NSCLC cells to EGFR-TKI dacomitinib by blocking autophagosome–lysosome fusion [142].…”

Section: Targeting Autophagy Overcomes Resistance To Anti-egfr Trementioning

confidence: 99%

Targeting Autophagy for Overcoming Resistance to Anti-EGFR Treatments

Kwon

Kim

Jung

et al. 2019

Cancers

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Epidermal growth factor receptor (EGFR) plays critical roles in cell proliferation, tumorigenesis, and anti-cancer drug resistance. Overexpression and somatic mutations of EGFR result in enhanced cancer cell survival. Therefore, EGFR can be a target for the development of anti-cancer therapy. Patients with cancers, including non-small cell lung cancers (NSCLC), have been shown to response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR antibodies. However, resistance to these anti-EGFR treatments has developed. Autophagy has emerged as a potential mechanism involved in the acquired resistance to anti-EGFR treatments. Anti-EGFR treatments can induce autophagy and result in resistance to anti-EGFR treatments. Autophagy is a programmed catabolic process stimulated by various stimuli. It promotes cellular survival under these stress conditions. Under normal conditions, EGFR-activated phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling inhibits autophagy while EGFR/rat sarcoma viral oncogene homolog (RAS)/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) signaling promotes autophagy. Thus, targeting autophagy may overcome resistance to anti-EGFR treatments. Inhibitors targeting autophagy and EGFR signaling have been under development. In this review, we discuss crosstalk between EGFR signaling and autophagy. We also assess whether autophagy inhibition, along with anti-EGFR treatments, might represent a promising approach to overcome resistance to anti-EGFR treatments in various cancers. In addition, we discuss new developments concerning anti-autophagy therapeutics for overcoming resistance to anti-EGFR treatments in various cancers.

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Silencing of secretory clusterin sensitizes NSCLC cells to V-ATPase inhibitors by downregulating survivin

Kim

Jin

Hong

et al. 2018

Biochemical and Biophysical Research Communications

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Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

Cited by 7 publications

References 35 publications

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

Leptomycin B reduces primary and acquired resistance of gefitinib in lung cancer cells

Targeting Autophagy for Overcoming Resistance to Anti-EGFR Treatments

Silencing of secretory clusterin sensitizes NSCLC cells to V-ATPase inhibitors by downregulating survivin

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