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Combined targeting of EGFR/HER promotes anti-tumor efficacy in subsets of KRAS mutant lung cancer resistant to single EGFR blockade

Ijeoma Adaku Umelo, Olivier De Wever UGent, Peter Kronenberger, Jan Van Deun UGent, Alfiah Noor, Kshitiz Singh, Erik Teugels, Gang Chen, Marc Bracke UGent and Jacques De Grève (2015) ONCOTARGET. 6(24). p.20132-20144
abstract
KRAS is a frequently mutated oncogene in lung cancer and among the most refractory to EGFR targeted therapy. Recently, preclinical evidence in pancreatic cancer has demonstrated that mutant KRAS can be regulated by EGFR. However, the distinct correlation between the EGFR/HER family members and mutant KRAS has not been investigated. Here, we show that non-small cell lung cancer cell lines harboring differing isoforms of mutant KRAS, can be broadly divided into EGFR/HER dependent and EGFR/HER independent groups. Combined therapeutic targeting of EGFR, HER2 and HER3 in isoforms regulated by extracellular growth signals promotes in vitro and in vivo efficacy. We also provide evidence that depletion of EGFR via RNA interference specifically abolishes the EGFR/KRAS interaction in the dependent subset. Taken together, these findings suggest that upstream inhibition of the EGFR/HER receptors may be effective in treating a subset of KRAS mutant lung cancers.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
KRAS, lung cancer, EGFR, HER, targeted therapy, INHIBITOR AZD6244 ARRY-142886, GROWTH-FACTOR RECEPTOR, K-RAS, RNA INTERFERENCE, CELLS, ERLOTINIB, PERTUZUMAB, GEFITINIB, THERAPY, 1ST-IN-HUMAN
journal title
ONCOTARGET
Oncotarget
volume
6
issue
24
pages
20132 - 20144
Web of Science type
Article
Web of Science id
000360138200039
JCR category
ONCOLOGY
JCR impact factor
5.008 (2015)
JCR rank
36/213 (2015)
JCR quartile
1 (2015)
ISSN
1949-2553
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
6896459
handle
http://hdl.handle.net/1854/LU-6896459
date created
2015-08-06 11:47:26
date last changed
2017-02-22 14:09:20
@article{6896459,
  abstract     = {KRAS is a frequently mutated oncogene in lung cancer and among the most refractory to EGFR targeted therapy. Recently, preclinical evidence in pancreatic cancer has demonstrated that mutant KRAS can be regulated by EGFR. However, the distinct correlation between the EGFR/HER family members and mutant KRAS has not been investigated. Here, we show that non-small cell lung cancer cell lines harboring differing isoforms of mutant KRAS, can be broadly divided into EGFR/HER dependent and EGFR/HER independent groups. Combined therapeutic targeting of EGFR, HER2 and HER3 in isoforms regulated by extracellular growth signals promotes in vitro and in vivo efficacy. We also provide evidence that depletion of EGFR via RNA interference specifically abolishes the EGFR/KRAS interaction in the dependent subset. Taken together, these findings suggest that upstream inhibition of the EGFR/HER receptors may be effective in treating a subset of KRAS mutant lung cancers.},
  author       = {Umelo, Ijeoma Adaku and De Wever, Olivier and Kronenberger, Peter and Van Deun, Jan and Noor, Alfiah and Singh, Kshitiz and Teugels, Erik and Chen, Gang and Bracke, Marc and De Gr{\`e}ve, Jacques},
  issn         = {1949-2553},
  journal      = {ONCOTARGET},
  keyword      = {KRAS,lung cancer,EGFR,HER,targeted therapy,INHIBITOR AZD6244 ARRY-142886,GROWTH-FACTOR RECEPTOR,K-RAS,RNA INTERFERENCE,CELLS,ERLOTINIB,PERTUZUMAB,GEFITINIB,THERAPY,1ST-IN-HUMAN},
  language     = {eng},
  number       = {24},
  pages        = {20132--20144},
  title        = {Combined targeting of EGFR/HER promotes anti-tumor efficacy in subsets of KRAS mutant lung cancer resistant to single EGFR blockade},
  volume       = {6},
  year         = {2015},
}

Chicago
Umelo, Ijeoma Adaku, Olivier De Wever, Peter Kronenberger, Jan Van Deun, Alfiah Noor, Kshitiz Singh, Erik Teugels, Gang Chen, Marc Bracke, and Jacques De Grève. 2015. “Combined Targeting of EGFR/HER Promotes Anti-tumor Efficacy in Subsets of KRAS Mutant Lung Cancer Resistant to Single EGFR Blockade.” Oncotarget 6 (24): 20132–20144.
APA
Umelo, I. A., De Wever, O., Kronenberger, P., Van Deun, J., Noor, A., Singh, K., Teugels, E., et al. (2015). Combined targeting of EGFR/HER promotes anti-tumor efficacy in subsets of KRAS mutant lung cancer resistant to single EGFR blockade. ONCOTARGET, 6(24), 20132–20144.
Vancouver
1.
Umelo IA, De Wever O, Kronenberger P, Van Deun J, Noor A, Singh K, et al. Combined targeting of EGFR/HER promotes anti-tumor efficacy in subsets of KRAS mutant lung cancer resistant to single EGFR blockade. ONCOTARGET. 2015;6(24):20132–44.
MLA
Umelo, Ijeoma Adaku, Olivier De Wever, Peter Kronenberger, et al. “Combined Targeting of EGFR/HER Promotes Anti-tumor Efficacy in Subsets of KRAS Mutant Lung Cancer Resistant to Single EGFR Blockade.” ONCOTARGET 6.24 (2015): 20132–20144. Print.