NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor

摘要: // Elena Galvani 1 , Jing Sun 2 Leticia G. Leon 3 Rocco Sciarrillo 1,4 Ravi S. Narayan 5 Robert Tjin Tham Sjin 6 Kwangho Lee Kadoaki Ohashi Danielle A.M. Heideman 7 Roberta R. Alfieri 8 Guus J. Heynen 9 Rene Bernards Egbert F. Smit 10 William Pao Godefridus Peters and Elisa Giovannetti 1,11 Department Medical Oncology, VU University Center, Amsterdam, The Netherlands Division of Hematology/Oncology, Medicine, Vanderbilt School Medicine Vanderbilt-Ingram Cancer Nashville, TN, USA Instituto de Tecnologias Biomedicas, Center for Biomedical Research the Canary Islands, La Laguna, Tenerife, Spain 4 Hematology, Radiation Celgene Avilomics Research, Bedford, MA, Pathology, Clinical Experimental Parma, Italy Molecular Carcinogenesis, Institute, Pulmonary Diseases, 11 Pharmacology Lab, AIRC Start-Up Unit, DIPINT, Pisa, Correspondence to: Giovannetti, email: Keywords : drug-resistance, EGFR-T790M, NSCLC, NF-κB, EMT Received January 10, 2015 Accepted April 08, Published 29, Abstract clinical efficacy EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) harbouring activating mutations is limited by emergence acquired resistance, mostly ascribed to secondary EGFR-T790M mutation. Selective have been proposed as a new, extremely relevant therapeutic approach. Here, we demonstrate that novel irreversible EGFR-TKI CNX-2006, structural analog CO-1686, currently tested phase-1/2 trial, active against vitro vivo NSCLC models expressing mutant EGFR, with minimal effect on wild-type receptor. By integration genetic functional analyses isogenic pairs provide evidence crucial role played NF-κB1 driving CNX-2006 resistance show NF-κB activation may replace oncogenic signaling when effective persistent inhibition target achieved presence T790M In this context, sole, either or pharmacologic, sufficient reduce viability cells adapted EGFR-TKIs. Overall, our findings support rational members pathway promising option patients who progress after treatment mutant-selective