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Differential gene expression induced by combined docetaxel and darolutamide in prostate cancer xenografts

ABSTRACT: A total of 64 NMRI nu/nu male mice (Janvier, Le Genest Saint Isle, France) were divided in four equal groups that underwent subcutaneous implantation of tumor fragments of PC346C, PC2400, PC2416 or PC2416-DEC. Tumor volume was measured twice weekly by calipers. At a tumor volume of 300 mm3, mice were randomized 1 to 1 to receive docetaxel once (33 mg/kg bodyweight, i.v.) and darolutamide q.d. (200 mg/kg bodyweight, p.o.) or both vehicles (5% glucose/EtOH/Polysorbate 80 8:1:1 (v/v/v) i.v. and PEG400/propylene glycol/5% glucose 5:3:2 (v/v/v) p.o., respectively) until tumor volume exceeded 1500 mm3 or for maximal 60 days, at which tumors were harvested and frozen. Drug dosages were based on a previously conducted safety experiment. One mouse was excluded from the analysis due to attrition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246920 | GEO | 2025/04/01

REPOSITORIES: GEO

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Project description:Transcriptome analysis was used to identify gene expression changes during development of sunitinib resistance in a renal cell carcinoma patient-derived xenograft (PDX) model. During the response phase, tumors exhibited a 91% reduction in volume, characterized by induction of TNFRSF1A, TNFAIP3, NFKB2, CCL2, CCL20, BIRC3, and MOAP1. Ingenuity Pathway Analysis indicated decreased expression of cell survival genes during tumor response to sunitinib. In this model, after 4 weeks of treatment, tumors developed resistance despite continued administration of the tyrosine kinase inhibitor (TKI) sunitinib (40 mg/kg/d p.o.). Resistance was associated with increased expression of VEGFA, EPO, IL-8, ANGPT2, TNFRSF12, MAPK3/7, MAPKBP1, and increased cell survival genes, suggesting activation of angiogenesis and MAPK/ERK pathways. Tumor lysate mRNA evaluated for murine gene expression to examine the contribution of host effects, indicated that tumor response was associated with downregulation of immune cell trafficking, cellular movement, and inflammatory response genes. During tumor escape, genes associated with cellular movement, inflammatory response, and immune cell trafficking were strongly induced, along with intratumoral accumulation of myeloid derived suppressor cells (MDSC), indicating a role for host factors during emergence of sunitinib resistance. The same PDX model was used to assess anti-tumor efficacy of sunitinib combined with MEK inhibitor (MEKi) PD-0325901 (4 mg/kg/d p.o.) using different schedules. The most effective treatment regimen was either continuous treatment with both drugs or switching from sunitinib to PD-0325901 monotherapy at d30, which reduced tumor volume by 78.6% (p=0.0241) and 88.5% (p=0.0068), respectively. The combination of MEKi with TKI (sunitinib, axitinib, or pazopanib) suppressed levels of phospho-MEK1/2 and phospho-ERK1/2, and decreased intratumoral MDSC. Thus, continuous treatment with sunitinib alone did not maintain tumor response, and addition of a MEKi abrogated resistance leading to prolonged survival.

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Differential gene expression induced by combined docetaxel and darolutamide in prostate cancer xenografts

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