Proteomics

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Optimized high-order drug mixtures improve colorectal carcinoma treatment via inactivationof MAP kinase signaling pathway and cell cycle alteration


ABSTRACT: Colorectal carcinoma is currently treated with a combination of chemotherapeutic drugs supplemented with targeted drugs. Since there is an eminent need to improved therapeutic success we employed the phenotypically-driven therapeutically guided multidrug optimization (TGMO) technology to identify personalized optimal drug combinations (ODCs). Using this technology we obtained low dose synergistic and selective ODCs for a panel of human colorectal carcinoma cells that remained active in 3-dimensional heterotypic co-culture models. From RNA sequencing and phosphoproteomics analysis we noticed considerable overlap in the top 20 most active kinases in all cell lines and that the mechanism converges around MAP kinase signaling and cell cycle inhibition despite differential cell mutation status, transcript expression levels and protein kinase activity. RNA sequencing revealed differentially expressed genes that confirmed these observations. These combinations were subsequently translated to in vivo models. Interestingly, the optimized drug mixtures reduced tumor volume with 80% and significantly outperformed the standard chemotherapy (FOLFOX) in these models, while preventing toxicity, observed after FOLFOX treatment. Pharmacokinetics studies demonstrated that the combinations supported significantly enhanced drug bioavailability.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colonic Epithelium

DISEASE(S): Colon Cancer

SUBMITTER: Sander Piersma  

LAB HEAD: Connie Ramona Jimenez

PROVIDER: PXD016604 | Pride | 2021-09-09

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
MQ_LYSATE.zip Other
MQ_pTyrIP.zip Other
QE3_190402_OPL4032_RdH_PNS_LYSATE_AB.raw Raw
QE3_190402_OPL4032_RdH_PNS_LYSATE_AC.raw Raw
QE3_190402_OPL4032_RdH_PNS_LYSATE_AD.raw Raw
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Publications


The current standard of care for colorectal cancer (CRC) is a combination of chemotherapeutics, often supplemented with targeted biological drugs. An urgent need exists for improved drug efficacy and minimized side effects, especially at late-stage disease. We employed the phenotypically driven therapeutically guided multidrug optimization (TGMO) technology to identify optimized drug combinations (ODCs) in CRC. We identified low-dose synergistic and selective ODCs for a panel of six human CRC ce  ...[more]

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