Oncotarget

Research Papers:

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

Elena Galvani, Jing Sun, Leticia G. Leon, Rocco Sciarrillo, Ravi S. Narayan, Robert Tjin Tham Sjin, Kwangho Lee, Kadoaki Ohashi, Daniëlle A.M. Heideman, Roberta R. Alfieri, Guus J. Heynen, René Bernards, Egbert F. Smit, William Pao, Godefridus J. Peters and Elisa Giovannetti _

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Oncotarget. 2015; 6:42717-42732. https://doi.org/10.18632/oncotarget.3956

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Abstract

Elena Galvani1, Jing Sun2, Leticia G. Leon3, Rocco Sciarrillo1,4, Ravi S. Narayan5, Robert Tjin Tham Sjin6, Kwangho Lee6, Kadoaki Ohashi2, Daniëlle A.M. Heideman7, Roberta R. Alfieri8, Guus J. Heynen9, René Bernards9, Egbert F. Smit10, William Pao2, Godefridus J. Peters1 and Elisa Giovannetti1,11

1 Department Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands

2 Division of Hematology/Oncology, Department of Medicine, Vanderbilt University School of Medicine and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA

3 Instituto de Tecnologias Biomedicas, Center for Biomedical Research of the Canary Islands, University of La Laguna, Tenerife, Spain

4 Department Hematology, VU University Medical Center, Amsterdam, The Netherlands

5 Department Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands

6 Celgene Avilomics Research, Bedford, MA, USA

7 Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands

8 Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy

9 Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands

10 Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands

11 Cancer Pharmacology Lab, AIRC Start-Up Unit, DIPINT, University of Pisa, Pisa, Italy

Correspondence to:

Elisa Giovannetti, email:

Keywords: drug-resistance, EGFR-T790M, NSCLC, NF-κB, EMT

Received: January 10, 2015 Accepted: April 08, 2015 Published: April 29, 2015

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.


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