Oncotarget

Research Papers:

Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR

Carminia Maria Della Corte, Umberto Malapelle, Elena Vigliar, Francesco Pepe, Giancarlo Troncone, Vincenza Ciaramella, Teresa Troiani, Erika Martinelli, Valentina Belli, Fortunato Ciardiello and Floriana Morgillo _

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Oncotarget. 2017; 8:23020-23032. https://doi.org/10.18632/oncotarget.15479

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Abstract

Carminia Maria Della Corte1, Umberto Malapelle2, Elena Vigliar2, Francesco Pepe2, Giancarlo Troncone2, Vincenza Ciaramella1, Teresa Troiani1, Erika Martinelli1, Valentina Belli1, Fortunato Ciardiello1, Floriana Morgillo1

1Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale “F. Magrassi e A. Lanzara,” Università degli studi della Campania “Luigi Vanvitelli”, Naples, Italy

2Dipartimento di Sanità Pubblica, Università degli Studi di Napoli Federico II, Naples, Italy

Correspondence to:

Floriana Morgillo, email: florianamorgillo@yahoo.com

Keywords: EGFR inhibitors, lung cancer, cell signalling, hedgehog, EMT

Received: January 13, 2017     Accepted: February 08, 2017     Published: February 18, 2017

ABSTRACT

Purpose: The aim of this work was to investigate the efficacy of sequential treatment with first-, second- and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and the mechanisms of acquired resistance occurring during the sequential use of these inhibitors.

Experimental design: We developed an in vivo model of acquired resistance to EGFR-inhibitors by treating nude mice xenografted with HCC827, a human non-small-cell lung cancer (NSCLC) cell line harboring EGFR activating mutation, with a sequence of first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) (erlotinib and gefitinib), of second-generation EGFR-TKI (afatinib) plus/minus the anti-EGFR monoclonal antibody cetuximab, and of third-generation EGFR-TKI (osimertinib).

Results: HCC827-derived xenografts and with acquired resistance to EGFR-inhibitors were sensitive to the sequential use of first-, second- and third-generation EGFR-TKIs. Continuous EGFR inhibition of first-generation resistant tumors by sequential treatment with afatinib plus/minus cetuximab, followed by osimertinib, represented an effective therapeutic strategy in this model. Whereas T790M resistance mutation was not detected, a major mechanism of acquired resistance was the activation of components of the Hedgehog (Hh) pathway. This phenomenon was accompanied by epithelial-to-mesenchymal transition. Cell lines established in vitro from gefitinib-, or afatinib- or osimertinib-resistant tumors showed metastatic properties and maintained EGFR-TKIs resistance in vitro, that was reverted by the combined blockade of Hh, with the selective SMO inhibitor sonidegib, and EGFR.

Conclusions: EGFR-mutant NSCLC can benefit from continuous treatment with EGFR-inhibitors, indepenently from mechanisms of resistance. In a complex and heterogenous scenario, Hh showed an important role in mediating resistance to EGFR-inhibitors through the induction of mesenchymal properties.


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