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MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model
- Source :
- British Journal of Cancer
- Publication Year :
- 2016
- Publisher :
- Nature Publishing Group, 2016.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
Cancer Research
Indoles
Cell
Mice, SCID
urologic and male genital diseases
Mice
0302 clinical medicine
tyrosine kinase inhibitor
Renal cell carcinoma
Mice, Inbred NOD
Sunitinib
Phosphorylation
Receptor
Mice, Knockout
Neovascularization, Pathologic
MEK inhibitor
Drug Synergism
female genital diseases and pregnancy complications
Kidney Neoplasms
3. Good health
Neoplasm Proteins
Tumor Burden
Gene Expression Regulation, Neoplastic
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Benzamides
Tyrosine kinase
medicine.drug
Adult
medicine.medical_specialty
renal cell carcinoma
MAP Kinase Signaling System
resistance
03 medical and health sciences
myeloid-derived suppressor cell
Internal medicine
Cell Line, Tumor
medicine
Carcinoma
Animals
Humans
Pyrroles
Carcinoma, Renal Cell
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase Kinases
business.industry
Myeloid-Derived Suppressor Cells
Diphenylamine
Receptors, Interleukin-2
medicine.disease
Xenograft Model Antitumor Assays
030104 developmental biology
Endocrinology
Cell culture
Drug Resistance, Neoplasm
Cancer research
Tumor Escape
business
Translational Therapeutics
transcriptome
Protein Processing, Post-Translational
Subjects
Details
- Language :
- English
- ISSN :
- 15321827 and 00070920
- Volume :
- 115
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- British Journal of Cancer
- Accession number :
- edsair.doi.dedup.....154c664aad13a060f9f52be41127373f