Tags

Type your tag names separated by a space and hit enter

YM155 sensitizes non-small cell lung cancer cells to EGFR-tyrosine kinase inhibitors through the mechanism of autophagy induction.
Biochim Biophys Acta Mol Basis Dis 2018; 1864(12):3786-3798BB

Abstract

Resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib and gefitinib, is a major clinical problem in the treatment of patients with non-small cell lung cancer (NSCLC). YM155 is a survivin small molecule inhibitor and has been demonstrated to induce cancer cell apoptosis and autophagy. EGFR-TKIs have been known to induce cancer cell autophagy. In this study, we showed that YM155 markedly enhanced the sensitivity of erlotinib to EGFR-TKI resistant NSCLC cell lines H1650 (EGFR exon 19 deletion and PTEN loss) and A549 (EGFR wild type and KRAS mutation) through inducing autophagy-dependent apoptosis and autophagic cell death. The effects of YM155 combined with erlotinib on apoptosis and autophagy inductions were more obvious than those of YM155 in combination with survivin knockdown by siRNA transfection, suggesting that YM155 induced autophagy and apoptosis in the NSCLC cells partially depend on survivin downregulation. Meanwhile, we found that the AKT/mTOR pathway is involved in modulation of survivin downregulation and autophagy induction caused by YM155. In addition, YM155 can induce DNA damage in H1650 and A549 cell lines. Moreover, combining erlotinib further augmented DNA damage by YM155, which were retarded by autophagy inhibitor 3MA, or knockdown of autophagy-related protein Beclin 1, revealing that YM155 induced DNA damage is autophagy-dependent. Similar results were also observed in vivo xenograft experiments. Therefore, combination of YM155 and erlotinib offers a promising therapeutic strategy in NSCLC with EGFR-TKI resistant phenotype.

Authors+Show Affiliations

Department of Radiation Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.Center of Medical Experiment, Affiliated Hospital of Jiangsu University, Zhenjiang, China.Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, China.Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.Department of Pulmonary Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China. Electronic address: lijian541226@163.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30315932

Citation

Dai, Chun-Hua, et al. "YM155 Sensitizes Non-small Cell Lung Cancer Cells to EGFR-tyrosine Kinase Inhibitors Through the Mechanism of Autophagy Induction." Biochimica Et Biophysica Acta. Molecular Basis of Disease, vol. 1864, no. 12, 2018, pp. 3786-3798.
Dai CH, Shu Y, Chen P, et al. YM155 sensitizes non-small cell lung cancer cells to EGFR-tyrosine kinase inhibitors through the mechanism of autophagy induction. Biochim Biophys Acta Mol Basis Dis. 2018;1864(12):3786-3798.
Dai, C. H., Shu, Y., Chen, P., Wu, J. N., Zhu, L. H., Yuan, R. X., ... Li, J. (2018). YM155 sensitizes non-small cell lung cancer cells to EGFR-tyrosine kinase inhibitors through the mechanism of autophagy induction. Biochimica Et Biophysica Acta. Molecular Basis of Disease, 1864(12), pp. 3786-3798. doi:10.1016/j.bbadis.2018.10.015.
Dai CH, et al. YM155 Sensitizes Non-small Cell Lung Cancer Cells to EGFR-tyrosine Kinase Inhibitors Through the Mechanism of Autophagy Induction. Biochim Biophys Acta Mol Basis Dis. 2018;1864(12):3786-3798. PubMed PMID: 30315932.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - YM155 sensitizes non-small cell lung cancer cells to EGFR-tyrosine kinase inhibitors through the mechanism of autophagy induction. AU - Dai,Chun-Hua, AU - Shu,Yang, AU - Chen,Ping, AU - Wu,Jian-Nong, AU - Zhu,Li-Haun, AU - Yuan,Rong-Xia, AU - Long,Wei-Guo, AU - Zhu,Yu-Min, AU - Li,Jian, Y1 - 2018/10/10/ PY - 2018/07/28/received PY - 2018/09/13/revised PY - 2018/10/08/accepted PY - 2018/10/14/pubmed PY - 2019/6/25/medline PY - 2018/10/14/entrez KW - Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) KW - Erlotinib KW - Non-small cell lung cancer KW - Resistance KW - Survivin KW - YM155 SP - 3786 EP - 3798 JF - Biochimica et biophysica acta. Molecular basis of disease JO - Biochim Biophys Acta Mol Basis Dis VL - 1864 IS - 12 N2 - Resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib and gefitinib, is a major clinical problem in the treatment of patients with non-small cell lung cancer (NSCLC). YM155 is a survivin small molecule inhibitor and has been demonstrated to induce cancer cell apoptosis and autophagy. EGFR-TKIs have been known to induce cancer cell autophagy. In this study, we showed that YM155 markedly enhanced the sensitivity of erlotinib to EGFR-TKI resistant NSCLC cell lines H1650 (EGFR exon 19 deletion and PTEN loss) and A549 (EGFR wild type and KRAS mutation) through inducing autophagy-dependent apoptosis and autophagic cell death. The effects of YM155 combined with erlotinib on apoptosis and autophagy inductions were more obvious than those of YM155 in combination with survivin knockdown by siRNA transfection, suggesting that YM155 induced autophagy and apoptosis in the NSCLC cells partially depend on survivin downregulation. Meanwhile, we found that the AKT/mTOR pathway is involved in modulation of survivin downregulation and autophagy induction caused by YM155. In addition, YM155 can induce DNA damage in H1650 and A549 cell lines. Moreover, combining erlotinib further augmented DNA damage by YM155, which were retarded by autophagy inhibitor 3MA, or knockdown of autophagy-related protein Beclin 1, revealing that YM155 induced DNA damage is autophagy-dependent. Similar results were also observed in vivo xenograft experiments. Therefore, combination of YM155 and erlotinib offers a promising therapeutic strategy in NSCLC with EGFR-TKI resistant phenotype. SN - 1879-260X UR - https://www.unboundmedicine.com/medline/citation/30315932/YM155_sensitizes_non_small_cell_lung_cancer_cells_to_EGFR_tyrosine_kinase_inhibitors_through_the_mechanism_of_autophagy_induction_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0925-4439(18)30392-2 DB - PRIME DP - Unbound Medicine ER -