title: Combined targeting of EGFR/HER promotes anti-tumor efficacy in subsets of KRAS mutant lung cancer resistant to single EGFR blockade.
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.
authors.affiliation: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Ijeoma Adaku
authors.initials: IA
authors.lastname: Umelo
authors.affiliation: Laboratory of Experimental Cancer Research and Department of Radiotherapy, Universitair Ziekenhuis Gent, Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
authors.affiliation: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, Universitair Ziekenhuis Brussel, Brussels, Belgium.|Laboratory of Biotechnology, Department of Healthcare, Erasmushogeschool Brussel, Brussels, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Kronenberger
authors.affiliation: Laboratory of Experimental Cancer Research and Department of Radiotherapy, Universitair Ziekenhuis Gent, Brussels, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Van Deun
authors.affiliation: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Alfiah
authors.initials: A
authors.lastname: Noor
authors.affiliation: Laboratory of Gene Therapy & Regenerative Medicine, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Kshitiz
authors.initials: K
authors.lastname: Singh
authors.affiliation: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Teugels
authors.affiliation: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Laboratory of Experimental Cancer Research and Department of Radiotherapy, Universitair Ziekenhuis Gent, Brussels, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Bracke
authors.affiliation: Laboratory of Molecular Oncology and Department of Medical Oncology, Oncologisch Centrum, Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: De Grève
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011897:Random Allocation; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); C485206:pertuzumab
keywords: EGFR; HER; KRAS; lung cancer; targeted therapy