Cargando…
MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model
BACKGROUND: Renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKI) typically respond initially, but usually develop resistance to therapy. We utilised transcriptome analysis to identify gene expression changes during development of sunitinib resistance in a RCC patient-der...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061902/ https://www.ncbi.nlm.nih.gov/pubmed/27560553 http://dx.doi.org/10.1038/bjc.2016.263 |
_version_ | 1782459666370920448 |
---|---|
author | Diaz-Montero, C Marcela Mao, Frances J Barnard, John Parker, Yvonne Zamanian-Daryoush, Maryam Pink, John J Finke, James H Rini, Brian I Lindner, Daniel J |
author_facet | Diaz-Montero, C Marcela Mao, Frances J Barnard, John Parker, Yvonne Zamanian-Daryoush, Maryam Pink, John J Finke, James H Rini, Brian I Lindner, Daniel J |
author_sort | Diaz-Montero, C Marcela |
collection | PubMed |
description | BACKGROUND: Renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKI) typically respond initially, but usually develop resistance to therapy. We utilised transcriptome analysis to identify gene expression changes during development of sunitinib resistance in a RCC patient-derived xenograft (PDX) model. METHODS: RCC tumours were harvested during pre-treatment, response and escape phases. Direct anti-proliferative effects of sunitinib plus MEK inhibitor were assessed. Activation status (phosphorylation) of MEK1/2 and ERK1/2 was determined, myeloid-derived suppressor cells (MDSC) sub-fractions were quantitated and G-CSF was measured by ELISA. RESULTS: During the response phase, tumours exhibited 91% reduction in volume, characterised by decreased expression of cell survival genes. After 4-week treatment, tumours developed resistance to sunitinib, associated with increased expression of pro-angiogenic and cell survival genes. During tumour escape, cellular movement, inflammatory response and immune cell trafficking genes were induced, along with intra-tumoural accumulation of MDSC. In this PDX model, either continuous treatment with sunitinib plus MEK inhibitor PD-0325901, or switching from sunitinib to PD-0325901 was effective. The combination of PD-0325901 with TKI suppressed intra-tumoural phospho-MEK1/2, phospho-ERK1/2 and MDSC. CONCLUSIONS: Continuous treatment with sunitinib alone did not maintain anti-tumour response; addition of MEK inhibitor abrogated resistance, leading to improved anti-tumour efficacy. |
format | Online Article Text |
id | pubmed-5061902 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50619022017-10-11 MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model Diaz-Montero, C Marcela Mao, Frances J Barnard, John Parker, Yvonne Zamanian-Daryoush, Maryam Pink, John J Finke, James H Rini, Brian I Lindner, Daniel J Br J Cancer Translational Therapeutics BACKGROUND: Renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKI) typically respond initially, but usually develop resistance to therapy. We utilised transcriptome analysis to identify gene expression changes during development of sunitinib resistance in a RCC patient-derived xenograft (PDX) model. METHODS: RCC tumours were harvested during pre-treatment, response and escape phases. Direct anti-proliferative effects of sunitinib plus MEK inhibitor were assessed. Activation status (phosphorylation) of MEK1/2 and ERK1/2 was determined, myeloid-derived suppressor cells (MDSC) sub-fractions were quantitated and G-CSF was measured by ELISA. RESULTS: During the response phase, tumours exhibited 91% reduction in volume, characterised by decreased expression of cell survival genes. After 4-week treatment, tumours developed resistance to sunitinib, associated with increased expression of pro-angiogenic and cell survival genes. During tumour escape, cellular movement, inflammatory response and immune cell trafficking genes were induced, along with intra-tumoural accumulation of MDSC. In this PDX model, either continuous treatment with sunitinib plus MEK inhibitor PD-0325901, or switching from sunitinib to PD-0325901 was effective. The combination of PD-0325901 with TKI suppressed intra-tumoural phospho-MEK1/2, phospho-ERK1/2 and MDSC. CONCLUSIONS: Continuous treatment with sunitinib alone did not maintain anti-tumour response; addition of MEK inhibitor abrogated resistance, leading to improved anti-tumour efficacy. Nature Publishing Group 2016-10-11 2016-08-25 /pmc/articles/PMC5061902/ /pubmed/27560553 http://dx.doi.org/10.1038/bjc.2016.263 Text en Copyright © 2016 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/4.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ |
spellingShingle | Translational Therapeutics Diaz-Montero, C Marcela Mao, Frances J Barnard, John Parker, Yvonne Zamanian-Daryoush, Maryam Pink, John J Finke, James H Rini, Brian I Lindner, Daniel J MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model |
title | MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model |
title_full | MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model |
title_fullStr | MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model |
title_full_unstemmed | MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model |
title_short | MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model |
title_sort | mek inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model |
topic | Translational Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061902/ https://www.ncbi.nlm.nih.gov/pubmed/27560553 http://dx.doi.org/10.1038/bjc.2016.263 |
work_keys_str_mv | AT diazmonterocmarcela mekinhibitionabrogatessunitinibresistanceinarenalcellcarcinomapatientderivedxenograftmodel AT maofrancesj mekinhibitionabrogatessunitinibresistanceinarenalcellcarcinomapatientderivedxenograftmodel AT barnardjohn mekinhibitionabrogatessunitinibresistanceinarenalcellcarcinomapatientderivedxenograftmodel AT parkeryvonne mekinhibitionabrogatessunitinibresistanceinarenalcellcarcinomapatientderivedxenograftmodel AT zamaniandaryoushmaryam mekinhibitionabrogatessunitinibresistanceinarenalcellcarcinomapatientderivedxenograftmodel AT pinkjohnj mekinhibitionabrogatessunitinibresistanceinarenalcellcarcinomapatientderivedxenograftmodel AT finkejamesh mekinhibitionabrogatessunitinibresistanceinarenalcellcarcinomapatientderivedxenograftmodel AT rinibriani mekinhibitionabrogatessunitinibresistanceinarenalcellcarcinomapatientderivedxenograftmodel AT lindnerdanielj mekinhibitionabrogatessunitinibresistanceinarenalcellcarcinomapatientderivedxenograftmodel |