ArticleCancer genomics & proteomics
Timescale-dependent Phosphoproteomic Remodeling and Motility-associated Adaptation under Chronic Cabozantinib Exposure in Renal Cell Carcinoma.
Article in Cancer genomics & proteomics. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
BACKGROUND/
aimCabozantinib is a multi-target tyrosine kinase inhibitor used in renal cell carcinoma (RCC), yet the exposure-dependent remodeling of phosphorylation networks under short-term MATERIALS AND
methodsRCC cells were subjected to acute (48 h) or chronic (>4-month) cabozantinib exposure. Dimethyl-labeling-based phosphoproteomics was used to quantify phosphosites and derive pathway- and kinase-substrate-level modules, integrated with functional enrichment, 2D-annotation and PTM-signature analyses, immunoblotting, migration, and Matrigel invasion assays.
resultsA total of 6,305 phosphosites were quantified. Acute cabozantinib exposure predominantly downregulated cell-cycle and CDK-associated phosphorylation, consistent with a broad cytostatic remodeling pattern, whereas chronic cabozantinib exposure produced a more selective redistribution enriched for adhesion- and stress-associated modules, including MAPK/AP-1/MAPKAPK2/HSPB1-linked signatures. Activation-loop MET phosphorylation (Y1234/1235) remained suppressed under both exposure conditions, while phosphorylation of MET at T977 increased under chronic cabozantinib treatment and was interpreted as site-specific regulation within the remodeled phosphorylation context rather than restoration of MET signaling activity. Motility features examined in the same cellular background showed pattern-specific differences: migration exhibited modest but significant increases with a larger effect size in chronically cabozantinib-exposed cells under drug treatment, whereas invasion was consistently higher in chronically cabozantinib-exposed cells than in parental cells across conditions without a marked treatment-specific change.
conclusionChronic cabozantinib exposure is characterized by sustained suppression of MET phosphorylation and a selective adhesion- and MAPK/AP-1-associated phosphorylation program, accompanied by modest, pattern-specific motility differences observed within the same signaling context. These findings provide a systems level framework for future mechanistic and
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