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; Peter Kronenberger; Jan Van Deun; Alfiah Noor; Kshitiz Singh; Erik Teugels; Gang Chen; Marc Bracke; Jacques De Grève

doi:10.18632/oncotarget.3853

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

Oncotarget. 2015 Aug 21;6(24):20132-44. doi: 10.18632/oncotarget.3853.

Authors

Affiliations

¹ Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, Universitair Ziekenhuis Brussel, Brussels, Belgium.
² Laboratory of Experimental Cancer Research and Department of Radiotherapy, Universitair Ziekenhuis Gent, Brussels, Belgium.
³ Laboratory of Biotechnology, Department of Healthcare, Erasmushogeschool Brussel, Brussels, Belgium.
⁴ Laboratory of Gene Therapy & Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium.

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: EGFR; HER; KRAS; lung cancer; targeted therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal, Humanized / administration & dosage
Antibodies, Monoclonal, Humanized / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / enzymology
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / pathology
Cell Proliferation / drug effects
ErbB Receptors / antagonists & inhibitors*
Erlotinib Hydrochloride / administration & dosage
Female
Genes, ras
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / enzymology
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Mice
Mice, Nude
Molecular Targeted Therapy
Mutation
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins p21(ras) / genetics*
Random Allocation
Signal Transduction
Xenograft Model Antitumor Assays

Substances

Antibodies, Monoclonal, Humanized
KRAS protein, human
Protein Kinase Inhibitors
Erlotinib Hydrochloride
EGFR protein, human
ErbB Receptors
Proto-Oncogene Proteins p21(ras)
pertuzumab