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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; Impact Journals LLC; Volume: 6; Issue: 24 Linguagem: Inglês

10.18632/oncotarget.3853

1949-2553

Ijeoma Adaku Umelo, Olivier De Wever, Peter Kronenberger, Jan Van Deun, Alfiah Noor, Kshitiz Singh, Erik Teugels, Gang Chen, Marc Bracke, Jacques De Grève,

Protein Kinase Regulation and GTPase Signaling

// Ijeoma Adaku Umelo 1 , Olivier De Wever 2 , Peter Kronenberger 1, 3 , Jan Van Deun 2 , Alfiah Noor 1 , Kshitiz Singh 4 , Erik Teugels 1 , Gang Chen 1 , Marc Bracke 2 , Jacques De Grève 1 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 Correspondence to: Jacques De Grève, e-mail: Jacques.Degreve@uzbrussel.be Keywords: lung cancer, KRAS, EGFR, HER, targeted therapy Received: December 09, 2014 Accepted: May 05, 2015 Published: May 15, 2015 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.