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244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells.
Oncotarget 2015; 6(42):44274-88O

Abstract

The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer(NSCLC). Several EGFR tyrosine kinase inhibitors(TKIs), such as gefitinib, have been used as effective clinical therapies for patients with NSCLC. Unfortunately, acquired resistance to gefitinib commonly occurs after 6-12 months of treatment. The resistance is associated with the appearance of the L858R/T790M double mutation of the EGFR. In our present study, we discovered a compound,referred to as 244-MPT, which could suppress either gefitinib-sensitive or -resistant lung cancer cell growth and colony formation, and also suppressed the kinase activity of both wildtype and double mutant (L858R/T790M) EGFR. The underlying mechanism reveals that 244-MPT could interact with either the wildtype or double-mutant EGFR in an ATP-competitive manner and inhibit activity. Treatment with 244-MPT could substantially reduce the phosphorylation of EGFR and its downstream signaling pathways, including Akt and ERK1/2 in gefitinib-sensitive and -resistant cell lines. It was equally effective in suppressing EGFR phosphorylation and downstream signaling in NL20 cells transfected with wildtype, single-mutant (L858R) or mutant (L858R/T790M) EGFR. 244-MPT could also induce apoptosis in a gefitinib-resistant cell line and strongly suppress gefitinib-resistant NSCLC tumor growth in a xenograft mouse model. In addition, 244-MPT could effectively reduce the size of tumors in a gefitinib-resistant NSCLC patient-derived xenograft (PDX) SCID mouse model. Overall, 244-MPT could overcome gefitinib-resistance by directly targeting the EGFR.

Authors+Show Affiliations

The Hormel Institute, University of Minnesota, Austin, MN, USA. Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China. The First Affiliated Hospital of Zhengzhou University, Henan, China. The China-US (Henan) Hormel Cancer Institute, Henan, China.The Hormel Institute, University of Minnesota, Austin, MN, USA. Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China. The China-US (Henan) Hormel Cancer Institute, Henan, China.The Hormel Institute, University of Minnesota, Austin, MN, USA. The First Affiliated Hospital of Zhengzhou University, Henan, China. The China-US (Henan) Hormel Cancer Institute, Henan, China.Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China.The Hormel Institute, University of Minnesota, Austin, MN, USA. Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China. The China-US (Henan) Hormel Cancer Institute, Henan, China.The First Affiliated Hospital of Zhengzhou University, Henan, China.The Hormel Institute, University of Minnesota, Austin, MN, USA.The Hormel Institute, University of Minnesota, Austin, MN, USA.The Hormel Institute, University of Minnesota, Austin, MN, USA. Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China. The Affiliated Cancer Hospital of Zhengzhou University, Henan, China.The Hormel Institute, University of Minnesota, Austin, MN, USA.The Hormel Institute, University of Minnesota, Austin, MN, USA.The Hormel Institute, University of Minnesota, Austin, MN, USA.Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China.The Hormel Institute, University of Minnesota, Austin, MN, USA. The China-US (Henan) Hormel Cancer Institute, Henan, China.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26517520

Citation

Zhang, Yi, et al. "244-MPT Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer Cells." Oncotarget, vol. 6, no. 42, 2015, pp. 44274-88.
Zhang Y, Yao K, Shi C, et al. 244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells. Oncotarget. 2015;6(42):44274-88.
Zhang, Y., Yao, K., Shi, C., Jiang, Y., Liu, K., Zhao, S., ... Dong, Z. (2015). 244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells. Oncotarget, 6(42), pp. 44274-88. doi:10.18632/oncotarget.6236.
Zhang Y, et al. 244-MPT Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer Cells. Oncotarget. 2015 Dec 29;6(42):44274-88. PubMed PMID: 26517520.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells. AU - Zhang,Yi, AU - Yao,Ke, AU - Shi,Chengcheng, AU - Jiang,Yanan, AU - Liu,Kangdong, AU - Zhao,Song, AU - Chen,Hanyong, AU - Reddy,Kanamata, AU - Zhang,Chengjuan, AU - Chang,Xiaoyu, AU - Ryu,Joohyun, AU - Bode,Ann M, AU - Dong,Ziming, AU - Dong,Zigang, PY - 2015/07/20/received PY - 2015/10/11/accepted PY - 2015/10/31/entrez PY - 2015/10/31/pubmed PY - 2016/11/8/medline KW - epidermal growth factor receptor (EGFR) KW - gefitinib resistance KW - non-small cell lung cancer (NSCLC) SP - 44274 EP - 88 JF - Oncotarget JO - Oncotarget VL - 6 IS - 42 N2 - The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer(NSCLC). Several EGFR tyrosine kinase inhibitors(TKIs), such as gefitinib, have been used as effective clinical therapies for patients with NSCLC. Unfortunately, acquired resistance to gefitinib commonly occurs after 6-12 months of treatment. The resistance is associated with the appearance of the L858R/T790M double mutation of the EGFR. In our present study, we discovered a compound,referred to as 244-MPT, which could suppress either gefitinib-sensitive or -resistant lung cancer cell growth and colony formation, and also suppressed the kinase activity of both wildtype and double mutant (L858R/T790M) EGFR. The underlying mechanism reveals that 244-MPT could interact with either the wildtype or double-mutant EGFR in an ATP-competitive manner and inhibit activity. Treatment with 244-MPT could substantially reduce the phosphorylation of EGFR and its downstream signaling pathways, including Akt and ERK1/2 in gefitinib-sensitive and -resistant cell lines. It was equally effective in suppressing EGFR phosphorylation and downstream signaling in NL20 cells transfected with wildtype, single-mutant (L858R) or mutant (L858R/T790M) EGFR. 244-MPT could also induce apoptosis in a gefitinib-resistant cell line and strongly suppress gefitinib-resistant NSCLC tumor growth in a xenograft mouse model. In addition, 244-MPT could effectively reduce the size of tumors in a gefitinib-resistant NSCLC patient-derived xenograft (PDX) SCID mouse model. Overall, 244-MPT could overcome gefitinib-resistance by directly targeting the EGFR. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/26517520/244_MPT_overcomes_gefitinib_resistance_in_non_small_cell_lung_cancer_cells_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=6236 DB - PRIME DP - Unbound Medicine ER -