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Title: Targeting SHP2 for EGFR inhibitor resistant non-small cell lung carcinoma

Abstract

Highlights: •SHP2 is required for EGFR inhibitor resistant NSCLC H1975 cell proliferation. •SHP2 inhibitor blocks EGF-stimulated ERK1/2 activation and proliferation. •SHP2 inhibitor exhibits marked anti-tumor activity in H1975 xenograft mice. •SHP2 inhibitor synergizes with PI3K inhibitor in suppressing cell growth. •Targeting SHP2 represents a novel strategy for EGFR inhibitor resistant NSCLCs. -- Abstract: Targeted therapy with inhibitors of epidermal growth factor receptor (EGFR) has produced a noticeable benefit to non-small cell lung cancer (NSCLC) patients whose tumors carry activating mutations (e.g. L858R) in EGFR. Unfortunately, these patients develop drug resistance after treatment, due to acquired secondary gatekeeper mutations in EGFR (e.g. T790M). Given the critical role of SHP2 in growth factor receptor signaling, we sought to determine whether targeting SHP2 could have therapeutic value for EGFR inhibitor resistant NSCLC. We show that SHP2 is required for EGF-stimulated ERK1/2 phosphorylation and proliferation in EGFR inhibitor resistant NSCLC cell line H1975, which harbors the EGFR T790M/L858R double-mutant. We demonstrate that treatment of H1975 cells with II-B08, a specific SHP2 inhibitor, phenocopies the observed growth inhibition and reduced ERK1/2 activation seen in cells treated with SHP2 siRNA. Importantly, we also find that II-B08 exhibits marked anti-tumor activity in H1975 xenograft mice. Finally, wemore » observe that combined inhibition of SHP2 and PI3K impairs both the ERK1/2 and PI3K/AKT signaling axes and produces significantly greater effects on repressing H1975 cell growth than inhibition of either protein individually. Collectively, these results suggest that targeting SHP2 may represent an effective strategy for treatment of EGFR inhibitor resistant NSCLCs.« less

Authors:
; ;  [1];  [1];  [1]
  1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis (United States)
Publication Date:
OSTI Identifier:
22242124
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 439; Journal Issue: 4; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARCINOMAS; CELL PROLIFERATION; DRUGS; GROWTH FACTORS; INHIBITION; LUNGS; MICE; MUTATIONS; PHOSPHORYLATION; RECEPTORS; THERAPY; TYROSINE

Citation Formats

Xu, Jie, Zeng, Li-Fan, Shen, Weihua, Turchi, John J., Department of Medicine, Indiana University School of Medicine, Indianapolis, and Zhang, Zhong-Yin. Targeting SHP2 for EGFR inhibitor resistant non-small cell lung carcinoma. United States: N. p., 2013. Web. doi:10.1016/J.BBRC.2013.09.028.
Xu, Jie, Zeng, Li-Fan, Shen, Weihua, Turchi, John J., Department of Medicine, Indiana University School of Medicine, Indianapolis, & Zhang, Zhong-Yin. Targeting SHP2 for EGFR inhibitor resistant non-small cell lung carcinoma. United States. https://doi.org/10.1016/J.BBRC.2013.09.028
Xu, Jie, Zeng, Li-Fan, Shen, Weihua, Turchi, John J., Department of Medicine, Indiana University School of Medicine, Indianapolis, and Zhang, Zhong-Yin. 2013. "Targeting SHP2 for EGFR inhibitor resistant non-small cell lung carcinoma". United States. https://doi.org/10.1016/J.BBRC.2013.09.028.
@article{osti_22242124,
title = {Targeting SHP2 for EGFR inhibitor resistant non-small cell lung carcinoma},
author = {Xu, Jie and Zeng, Li-Fan and Shen, Weihua and Turchi, John J. and Department of Medicine, Indiana University School of Medicine, Indianapolis and Zhang, Zhong-Yin},
abstractNote = {Highlights: •SHP2 is required for EGFR inhibitor resistant NSCLC H1975 cell proliferation. •SHP2 inhibitor blocks EGF-stimulated ERK1/2 activation and proliferation. •SHP2 inhibitor exhibits marked anti-tumor activity in H1975 xenograft mice. •SHP2 inhibitor synergizes with PI3K inhibitor in suppressing cell growth. •Targeting SHP2 represents a novel strategy for EGFR inhibitor resistant NSCLCs. -- Abstract: Targeted therapy with inhibitors of epidermal growth factor receptor (EGFR) has produced a noticeable benefit to non-small cell lung cancer (NSCLC) patients whose tumors carry activating mutations (e.g. L858R) in EGFR. Unfortunately, these patients develop drug resistance after treatment, due to acquired secondary gatekeeper mutations in EGFR (e.g. T790M). Given the critical role of SHP2 in growth factor receptor signaling, we sought to determine whether targeting SHP2 could have therapeutic value for EGFR inhibitor resistant NSCLC. We show that SHP2 is required for EGF-stimulated ERK1/2 phosphorylation and proliferation in EGFR inhibitor resistant NSCLC cell line H1975, which harbors the EGFR T790M/L858R double-mutant. We demonstrate that treatment of H1975 cells with II-B08, a specific SHP2 inhibitor, phenocopies the observed growth inhibition and reduced ERK1/2 activation seen in cells treated with SHP2 siRNA. Importantly, we also find that II-B08 exhibits marked anti-tumor activity in H1975 xenograft mice. Finally, we observe that combined inhibition of SHP2 and PI3K impairs both the ERK1/2 and PI3K/AKT signaling axes and produces significantly greater effects on repressing H1975 cell growth than inhibition of either protein individually. Collectively, these results suggest that targeting SHP2 may represent an effective strategy for treatment of EGFR inhibitor resistant NSCLCs.},
doi = {10.1016/J.BBRC.2013.09.028},
url = {https://www.osti.gov/biblio/22242124}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 4,
volume = 439,
place = {United States},
year = {Fri Oct 04 00:00:00 EDT 2013},
month = {Fri Oct 04 00:00:00 EDT 2013}
}