title: NF-κB drives acquired resistance to a novel mutant-selective EGFR inhibitor.
abstract: The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations is limited by the emergence of acquired resistance, mostly ascribed to the secondary EGFR-T790M mutation. Selective EGFR-T790M inhibitors have been proposed as a new, extremely relevant therapeutic approach. Here, we demonstrate that the novel irreversible EGFR-TKI CNX-2006, a structural analog of CO-1686, currently tested in a phase-1/2 trial, is active against in vitro and in vivo NSCLC models expressing mutant EGFR, with minimal effect on the wild-type receptor. By integration of genetic and functional analyses in isogenic cell pairs we provide evidence of the crucial role played by NF-κB1 in driving CNX-2006 acquired resistance and show that NF-κB activation may replace the oncogenic EGFR signaling in NSCLC when effective and persistent inhibition of the target is achieved in the presence of the T790M mutation. In this context, we demonstrate that the sole, either genetic or pharmacologic, inhibition of NF-κB is sufficient to reduce the viability of cells that adapted to EGFR-TKIs. Overall, our findings support the rational inhibition of members of the NF-κB pathway as a promising therapeutic option for patients who progress after treatment with novel mutant-selective EGFR-TKIs.
authors.affiliation: Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Elena
authors.initials: E
authors.lastname: Galvani
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Vanderbilt University School of Medicine and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Instituto de Tecnologias Biomedicas, Center for Biomedical Research of the Canary Islands, University of La Laguna, Tenerife, Spain.
authors.forename: Leticia G
authors.initials: LG
authors.lastname: Leon
authors.affiliation: Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.|Department Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Rocco
authors.initials: R
authors.lastname: Sciarrillo
authors.affiliation: Department Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Narayan
authors.affiliation: Celgene Avilomics Research, Bedford, MA, USA.
authors.forename: Robert Tjin Tham
authors.initials: RT
authors.lastname: Sjin
authors.affiliation: Celgene Avilomics Research, Bedford, MA, USA.
authors.forename: Kwangho
authors.initials: K
authors.lastname: Lee
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Vanderbilt University School of Medicine and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: Kadoaki
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Roberta R
authors.initials: RR
authors.lastname: Alfieri
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Guus J
authors.initials: GJ
authors.lastname: Heynen
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Bernards
authors.affiliation: Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Vanderbilt University School of Medicine and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.affiliation: Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.affiliation: Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.|Cancer Pharmacology Lab, AIRC Start-Up Unit, DIPINT, University of Pisa, Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001384:Azetidines / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D001384:Azetidines; C000611378:CNX-2006; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; C000589977:rociletinib; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR-T790M; EMT; NF-κB; NSCLC; drug-resistance