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Optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment

Beijnum, Judy R.
Weiss, Andrea
Piersma, Sander R.
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Published in Molecular oncology. 2020
Abstract 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 cell lines also active in heterotypic 3D co‐culture models. Transcriptome sequencing and phosphoproteome analyses showed that the mechanisms of action of these ODCs converged toward MAP kinase signaling and cell cycle inhibition. Two cell‐specific ODCs were translated to in vivo mouse models. The ODCs reduced tumor growth by ~80%, outperforming standard chemotherapy (FOLFOX). No toxicity was observed for the ODCs, while significant side effects were induced in the group treated with FOLFOX therapy. Identified ODCs demonstrated significantly enhanced bioavailability of the individual components. Finally, ODCs were also active in primary cells from CRC patient tumor tissues. Taken together, we show that the TGMO technology efficiently identifies selective and potent low‐dose drug combinations, optimized regardless of tumor mutation status, outperforming conventional chemotherapy.
Keywords Colorectal carcinomaCombinationTreatmentDrug–drug interactionsDrug–Target interactionsPhosphoproteomicsSynergy
PMID: 33021054
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Research groups Groupe Desmeules Jules (pharmacologie/toxicologie) (567)
Immunothérapie des cancers (42)
Lymphomes MALT et réplication virale (807)
Métastases du foie (657)
Pharmaco-omiques et médecine de précision (1003)
Pharmacologie moléculaire
Transplantation et hépatologie (905)
European Commission: OPTIM
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ZOETEMELK, Marloes et al. Optimized low‐dose combinatorial drug treatment boosts selectivity and efficacy of colorectal carcinoma treatment. In: Molecular Oncology, 2020. doi: 10.1002/1878-0261.12797 https://archive-ouverte.unige.ch/unige:142854

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Deposited on : 2020-10-12

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