Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783421992093876224 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6537372 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT lamonicasilvia thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT minariroberta thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT cretelladaniele thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT flamminilisa thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT fumarolaclaudia thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT bonellimara thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT cavazzoniandrea thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT digiacomograziana thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT galettimaricla thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT madeddudenise thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT falcoangela thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT lagrastacostanzaannamaria thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT squadrillianna thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT barocellielisabetta thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT romanelalessandro thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT quainifederico thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT petroninipiergiorgio thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT tiseomarcello thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc AT alfieriroberta thirdgenerationegfrinhibitorosimertinibcombinedwithpemetrexedorcisplatinexertslonglastingantitumoreffectinegfrmutatedpreclinicalmodelsofnsclc |