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Transcriptomic analysis of the effects of mTOR inhibitor everolimus, CDK8/19 inhibitor SNX631 and their combination in MDA-MB-468 xenografts

ABSTRACT: RNA-Seq analysis was carried out to investigate the transcriptomic changes associated with the development of in vivo everolimus resistance and the effects of CDK8/19 inhibition on the development of resistance in MDA-MB-468 TNBC xenografts. In one study (short-term), tumor samples were collected after 30-40 days of treatment with vehicle or everolimus, when the tumor growth was still suppressed by the mTOR inhibitor. In another study (long-term), tumor samples were collected after 60-153 days of treatment with vehicle, everolimus, CDK8/19 inhibitor SNX631 or their combination, when tumors treated with everolimus but not with the drug combination developed resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271325 | GEO | 2024/10/31

REPOSITORIES: GEO

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Project description:Glomerular podocytes are highly differentiated cells that are key components of the kidney filtration units. The podocyte cytoskeleton builds the basis for the dynamic podocyte cytoarchitecture and plays a central role for proper podocyte function. Recent studies implicate that immunosuppressive agents including the mTOR-inhibitor everolimus have a protective role directly on the stability of the podocyte cytoskeleton. To elucidate mechanisms underlying mTOR-inhibitor mediated cytoskeletal rearrangements, we carried out microarray gene expression studies to identify target genes and corresponding pathways in response to everolimus. We analyzed the effect of everolimus in a puromycin aminonucleoside experimental in vitro model of podocyte injury. Upon treatment with puromycin aminonucleoside, microarray analysis revealed gene clusters involving cytoskeletal-associated pathways, adhesion, migration and extracellular matrix composition to be affected. Everolimus is capable of protecting podocytes from injury, both on the transcriptome and protein level. Rescued genes included TUBB2B and DCDC2, both involved in microtubule structure formation in neuronal cells but not identified in podocytes so far. Confirming gene expression data, Western-blot analysis in cultured podocytes showed an increase of TUBB2B and DCDC2 protein after everolimus treatment, and immunohistochemistry in healthy control kidneys confirmed a podocyte-specific expression. Microtubule-inhibitor experiments led to a maldistribution of TUBB2B and DCDC2 as well as an aberrant reorganization of the actin cytoskeleton. Tubb2bbrdp/brdp mice showed a delay in glomerular podocyte and capillary development. Taken together, our study suggests that off-target, non-immune mediated effects of the mTOR-inhibitor everolimus on the podocyte cytoskeleton might involve regulation of microtubules, revealing a potential novel role of TUBB2B and DCDC2 in glomerular podocyte development We analyzed the effect of everolimus on gene expression in a puromycin aminonucleoside experimental in vitro model of podocyte injury using microarrays

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Transcriptomic analysis of the effects of mTOR inhibitor everolimus, CDK8/19 inhibitor SNX631 and their combination in MDA-MB-468 xenografts

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