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

Content Provider	Europe PMC
Author	Zhang, Yi Yao, Ke Shi, Chengcheng Jiang, Yanan Liu, Kangdong Zhao, Song Chen, Hanyong Reddy, Kanamata Zhang, Chengjuan Chang, Xiaoyu Ryu, Joohyun Bode, Ann M. Dong, Ziming Dong, Zigang
Copyright Year	2015
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.
Journal	Oncotarget
Volume Number	6
PubMed Central reference number	PMC4792556
Issue Number	42
PubMed reference number	26517520
e-ISSN	19492553
DOI	10.18632/oncotarget.6236
Language	English
Publisher	Impact Journals LLC
Publisher Date	2015-12-01
Access Restriction	Open
Rights License	This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: © 2015 Zhang et al.
Subject Keyword	gefitinib resistance non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR)
Content Type	Text
Resource Type	Article
Subject	Oncology