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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

(2015) ONCOTARGET. 6(24). p.20132-20144
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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.
Keywords
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

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Citation

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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.
@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},
}

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