Efficacy of continuous EGFR-inhibition and role of Hedgehog in EGFR acquired resistance in human lung cancer cells with activating mutation of EGFR
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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
Floriana Morgillo, email: [email protected]
Keywords: EGFR inhibitors, lung cancer, cell signalling, hedgehog, EMT
Received: January 13, 2017 Accepted: February 08, 2017 Published: February 18, 2017
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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