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Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC

BACKGROUND: The third generation Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) osimertinib has been initially approved for T790M positive Non-Small Cell Lung Cancer (NSCLC) and more recently for first-line treatment of EGFR-mutant T790M negative NSCLC patients. Similarly to...

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Autores principales: La Monica, Silvia, Minari, Roberta, Cretella, Daniele, Flammini, Lisa, Fumarola, Claudia, Bonelli, Mara, Cavazzoni, Andrea, Digiacomo, Graziana, Galetti, Maricla, Madeddu, Denise, Falco, Angela, Lagrasta, Costanza Annamaria, Squadrilli, Anna, Barocelli, Elisabetta, Romanel, Alessandro, Quaini, Federico, Petronini, Pier Giorgio, Tiseo, Marcello, Alfieri, Roberta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537372/
https://www.ncbi.nlm.nih.gov/pubmed/31138260
http://dx.doi.org/10.1186/s13046-019-1240-x
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author La Monica, Silvia
Minari, Roberta
Cretella, Daniele
Flammini, Lisa
Fumarola, Claudia
Bonelli, Mara
Cavazzoni, Andrea
Digiacomo, Graziana
Galetti, Maricla
Madeddu, Denise
Falco, Angela
Lagrasta, Costanza Annamaria
Squadrilli, Anna
Barocelli, Elisabetta
Romanel, Alessandro
Quaini, Federico
Petronini, Pier Giorgio
Tiseo, Marcello
Alfieri, Roberta
author_facet La Monica, Silvia
Minari, Roberta
Cretella, Daniele
Flammini, Lisa
Fumarola, Claudia
Bonelli, Mara
Cavazzoni, Andrea
Digiacomo, Graziana
Galetti, Maricla
Madeddu, Denise
Falco, Angela
Lagrasta, Costanza Annamaria
Squadrilli, Anna
Barocelli, Elisabetta
Romanel, Alessandro
Quaini, Federico
Petronini, Pier Giorgio
Tiseo, Marcello
Alfieri, Roberta
author_sort La Monica, Silvia
collection PubMed
description BACKGROUND: The third generation Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) osimertinib has been initially approved for T790M positive Non-Small Cell Lung Cancer (NSCLC) and more recently for first-line treatment of EGFR-mutant T790M negative NSCLC patients. Similarly to previous generation TKIs, despite the high response rate, disease progression eventually occurs and current clinical research is focused on novel strategies to delay the emergence of osimertinib resistance. In this study we investigated the combination of osimertinib with pemetrexed or cisplatin in EGFR-mutated NSCLC cell lines and xenografts. METHODS: Tumor growth was evaluated in a PC9T790M xenograft model and tissue composition was morphometrically determined. PC9, PC9T790M and HCC827 cell lines were employed to test the efficacy of osimertinib and chemotherapy combination in vitro. Cell viability and cell death were evaluated by MTT assay and fluorescence microscopy. Protein expression and gene status were analysed by Western blotting, fluorescence in situ hybridization analysis, next-generation sequencing and digital droplet PCR. RESULTS: In xenograft models, osimertinib significantly inhibited tumor growth, however, as expected, in 50% of mice drug-resistance developed. A combination of osimertinib with pemetrexed or cisplatin prevented or at least delayed the onset of resistance. Interestingly, such combinations increased the fraction of fibrotic tissue and exerted a long-lasting activity after stopping therapy. In vitro studies demonstrated the stronger efficacy of the combination over the single treatments in inhibiting cell proliferation and inducing cell death in PC9T790M cells as well as in T790M negative PC9 and HCC827 cell lines, suggesting the potential role of this strategy also as first-line treatment. Finally, we demonstrated that osimertinib resistant clones, either derived from resistant tumors or generated in vitro, were less sensitive to pemetrexed prompting to use a chemotherapy regimen non-containing pemetrexed in patients after progression to osimertinib treatment. CONCLUSIONS: Our results identify a combination between osimertinib and pemetrexed or cisplatin potentially useful in the treatment of EGFR-mutated NSCLC patients, which might delay the appearance of osimertinib resistance with long-lasting effects. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1240-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-65373722019-05-30 Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC La Monica, Silvia Minari, Roberta Cretella, Daniele Flammini, Lisa Fumarola, Claudia Bonelli, Mara Cavazzoni, Andrea Digiacomo, Graziana Galetti, Maricla Madeddu, Denise Falco, Angela Lagrasta, Costanza Annamaria Squadrilli, Anna Barocelli, Elisabetta Romanel, Alessandro Quaini, Federico Petronini, Pier Giorgio Tiseo, Marcello Alfieri, Roberta J Exp Clin Cancer Res Research BACKGROUND: The third generation Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) osimertinib has been initially approved for T790M positive Non-Small Cell Lung Cancer (NSCLC) and more recently for first-line treatment of EGFR-mutant T790M negative NSCLC patients. Similarly to previous generation TKIs, despite the high response rate, disease progression eventually occurs and current clinical research is focused on novel strategies to delay the emergence of osimertinib resistance. In this study we investigated the combination of osimertinib with pemetrexed or cisplatin in EGFR-mutated NSCLC cell lines and xenografts. METHODS: Tumor growth was evaluated in a PC9T790M xenograft model and tissue composition was morphometrically determined. PC9, PC9T790M and HCC827 cell lines were employed to test the efficacy of osimertinib and chemotherapy combination in vitro. Cell viability and cell death were evaluated by MTT assay and fluorescence microscopy. Protein expression and gene status were analysed by Western blotting, fluorescence in situ hybridization analysis, next-generation sequencing and digital droplet PCR. RESULTS: In xenograft models, osimertinib significantly inhibited tumor growth, however, as expected, in 50% of mice drug-resistance developed. A combination of osimertinib with pemetrexed or cisplatin prevented or at least delayed the onset of resistance. Interestingly, such combinations increased the fraction of fibrotic tissue and exerted a long-lasting activity after stopping therapy. In vitro studies demonstrated the stronger efficacy of the combination over the single treatments in inhibiting cell proliferation and inducing cell death in PC9T790M cells as well as in T790M negative PC9 and HCC827 cell lines, suggesting the potential role of this strategy also as first-line treatment. Finally, we demonstrated that osimertinib resistant clones, either derived from resistant tumors or generated in vitro, were less sensitive to pemetrexed prompting to use a chemotherapy regimen non-containing pemetrexed in patients after progression to osimertinib treatment. CONCLUSIONS: Our results identify a combination between osimertinib and pemetrexed or cisplatin potentially useful in the treatment of EGFR-mutated NSCLC patients, which might delay the appearance of osimertinib resistance with long-lasting effects. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1240-x) contains supplementary material, which is available to authorized users. BioMed Central 2019-05-28 /pmc/articles/PMC6537372/ /pubmed/31138260 http://dx.doi.org/10.1186/s13046-019-1240-x Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
La Monica, Silvia
Minari, Roberta
Cretella, Daniele
Flammini, Lisa
Fumarola, Claudia
Bonelli, Mara
Cavazzoni, Andrea
Digiacomo, Graziana
Galetti, Maricla
Madeddu, Denise
Falco, Angela
Lagrasta, Costanza Annamaria
Squadrilli, Anna
Barocelli, Elisabetta
Romanel, Alessandro
Quaini, Federico
Petronini, Pier Giorgio
Tiseo, Marcello
Alfieri, Roberta
Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC
title Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC
title_full Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC
title_fullStr Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC
title_full_unstemmed Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC
title_short Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC
title_sort third generation egfr inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in egfr-mutated pre-clinical models of nsclc
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537372/
https://www.ncbi.nlm.nih.gov/pubmed/31138260
http://dx.doi.org/10.1186/s13046-019-1240-x
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