Research Papers:

244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells

Yi Zhang, Ke Yao, Chengcheng Shi, Yanan Jiang, Kangdong Liu, Song Zhao, Hanyong Chen, Kanamata Reddy, Chengjuan Zhang, Xiaoyu Chang, Joohyun Ryu, Ann M. Bode, Ziming Dong and Zigang Dong _

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Oncotarget. 2015; 6:44274-44288. https://doi.org/10.18632/oncotarget.6236

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Yi Zhang1,2,3,4,*, Ke Yao1,2,4,*, Chengcheng Shi1,3,4,*, Yanan Jiang2,*, Kangdong Liu1,2,4, Song Zhao3, Hanyong Chen1, Kanamata Reddy1, Chengjuan Zhang1,2,5, Xiaoyu Chang1, Joohyun Ryu1, Ann M. Bode1, Ziming Dong2, Zigang Dong1,4

1The Hormel Institute, University of Minnesota, Austin, MN, USA

2Pathophysiology Department, Basic Medical College, Zhengzhou University, Henan, China

3The First Affiliated Hospital of Zhengzhou University, Henan, China

4The China-US (Henan) Hormel Cancer Institute, Henan, China

5The Affiliated Cancer Hospital of Zhengzhou University, Henan, China

*These authors have contributed equally to this work

Correspondence to:

Zigang Dong, e-mail: zgdong@hi.umn.edu

Ziming Dong, e-mail: dongzm@zzu.edu.cn

Keywords: gefitinib resistance, non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR)

Received: July 20, 2015     Accepted: October 11, 2015     Published: October 26, 2015


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.

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