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; Zigang Dong

doi:10.18632/oncotarget.6236

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, Zigang Dong

The Hormel Institute

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Pages (from-to)	44274-44288
Number of pages	15
Journal	Oncotarget
Volume	6
Issue number	42
DOIs	https://doi.org/10.18632/oncotarget.6236
State	Published - 2015

Bibliographical note

Funding Information:
The authors thank Todd Schuster and Alyssa Langfald for supporting experiments, Katrina Plueger for animal experiments and Nicki Brickman for assistance in submitting our manuscript (The Hormel Institute, University of Minnesota). This work was supported by National Institutes of Health grants: CA166011 (Z. Dong), CA172457 (Z. Dong), R37 CA81064 (Z. Dong), and CA187027 (Z. Dong), The Hormel Foundation, and National Natural Science Foundation of China, NSFC Number: 81000926 (Z. Dong).

Keywords

Epidermal growth factor receptor (EGFR)
Gefitinib resistance
Non-small cell lung cancer (NSCLC)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.18632/oncotarget.6236

Find It

Find It at U of M Libraries

Cite this

@article{246e423264014e388dafe1b5e818aad3,

title = "244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells",

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.",

keywords = "Epidermal growth factor receptor (EGFR), Gefitinib resistance, Non-small cell lung cancer (NSCLC)",

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

note = "Funding Information: The authors thank Todd Schuster and Alyssa Langfald for supporting experiments, Katrina Plueger for animal experiments and Nicki Brickman for assistance in submitting our manuscript (The Hormel Institute, University of Minnesota). This work was supported by National Institutes of Health grants: CA166011 (Z. Dong), CA172457 (Z. Dong), R37 CA81064 (Z. Dong), and CA187027 (Z. Dong), The Hormel Foundation, and National Natural Science Foundation of China, NSFC Number: 81000926 (Z. Dong).",

year = "2015",

doi = "10.18632/oncotarget.6236",

language = "English (US)",

volume = "6",

pages = "44274--44288",

journal = "Oncotarget",

issn = "1949-2553",

publisher = "Impact Journals",

number = "42",

}

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

N1 - Funding Information: The authors thank Todd Schuster and Alyssa Langfald for supporting experiments, Katrina Plueger for animal experiments and Nicki Brickman for assistance in submitting our manuscript (The Hormel Institute, University of Minnesota). This work was supported by National Institutes of Health grants: CA166011 (Z. Dong), CA172457 (Z. Dong), R37 CA81064 (Z. Dong), and CA187027 (Z. Dong), The Hormel Foundation, and National Natural Science Foundation of China, NSFC Number: 81000926 (Z. Dong).

PY - 2015

Y1 - 2015

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.

AB - 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.

KW - Epidermal growth factor receptor (EGFR)

KW - Gefitinib resistance

KW - Non-small cell lung cancer (NSCLC)

UR - http://www.scopus.com/inward/record.url?scp=84953397160&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84953397160&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.6236

DO - 10.18632/oncotarget.6236

M3 - Article

C2 - 26517520

AN - SCOPUS:84953397160

SN - 1949-2553

VL - 6

SP - 44274

EP - 44288

JO - Oncotarget

JF - Oncotarget

IS - 42

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this