Drug resistance mechanisms in colorectal cancer dissected with cell type-specific dynamic logic models

F. Eduati, V. Doldàn-Martelli, B. Klinger, T. Cokelaer, A. Sieber, F. Kogera, M. Dorel, M.J. Garnett, N. Blüthgen, J. Saez-Rodriguez

Onderzoeksoutput: Bijdrage aan tijdschriftTijdschriftartikelAcademicpeer review

26 Citaties (Scopus)

Uittreksel

Genomic features are used as biomarkers of sensitivity to kinase inhibitors used widely to treat human cancer, but effective patient stratification based on these principles remains limited in impact. Insofar as kinase inhibitors interfere with signaling dynamics, and, in turn, signaling dynamics affects inhibitor responses, we investigated associations in this study between cell-specific dynamic signaling pathways and drug sensitivity. Specifically, we measured 14 phosphoproteins under 43 different perturbed conditions (combinations of 5 stimuli and 7 inhibitors) in 14 colorectal cancer cell lines, building cell line-specific dynamic logic models of underlying signaling networks. Model parameters representing pathway dynamics were used as features to predict sensitivity to a panel of 27 drugs. Specific parameters of signaling dynamics correlated strongly with drug sensitivity for 14 of the drugs, 9 of which had no genomic biomarker. Following one of these associations, we validated a drug combination predicted to overcome resistance to MEK inhibitors by coblockade of GSK3, which was not found based on associations with genomic data. These results suggest that to better understand the cancer resistance and move toward personalized medicine, it is essential to consider signaling network dynamics that cannot be inferred from static genotypes.

TaalEngels
Pagina's3364-3375
Aantal pagina's12
TijdschriftCancer Research
Volume77
Nummer van het tijdschrift12
DOI's
StatusGepubliceerd - 15 jun 2017
Extern gepubliceerdJa

Vingerafdruk

Drug Resistance
Colorectal Neoplasms
Pharmaceutical Preparations
Phosphotransferases
Biomarkers
Cell Line
Precision Medicine
Phosphoproteins
Mitogen-Activated Protein Kinase Kinases
Drug Combinations
Neoplasms
Genotype

Citeer dit

Eduati, F., Doldàn-Martelli, V., Klinger, B., Cokelaer, T., Sieber, A., Kogera, F., ... Saez-Rodriguez, J. (2017). Drug resistance mechanisms in colorectal cancer dissected with cell type-specific dynamic logic models. Cancer Research, 77(12), 3364-3375. DOI: 10.1158/0008-5472.CAN-17-0078
Eduati, F. ; Doldàn-Martelli, V. ; Klinger, B. ; Cokelaer, T. ; Sieber, A. ; Kogera, F. ; Dorel, M. ; Garnett, M.J. ; Blüthgen, N. ; Saez-Rodriguez, J./ Drug resistance mechanisms in colorectal cancer dissected with cell type-specific dynamic logic models. In: Cancer Research. 2017 ; Vol. 77, Nr. 12. blz. 3364-3375
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abstract = "Genomic features are used as biomarkers of sensitivity to kinase inhibitors used widely to treat human cancer, but effective patient stratification based on these principles remains limited in impact. Insofar as kinase inhibitors interfere with signaling dynamics, and, in turn, signaling dynamics affects inhibitor responses, we investigated associations in this study between cell-specific dynamic signaling pathways and drug sensitivity. Specifically, we measured 14 phosphoproteins under 43 different perturbed conditions (combinations of 5 stimuli and 7 inhibitors) in 14 colorectal cancer cell lines, building cell line-specific dynamic logic models of underlying signaling networks. Model parameters representing pathway dynamics were used as features to predict sensitivity to a panel of 27 drugs. Specific parameters of signaling dynamics correlated strongly with drug sensitivity for 14 of the drugs, 9 of which had no genomic biomarker. Following one of these associations, we validated a drug combination predicted to overcome resistance to MEK inhibitors by coblockade of GSK3, which was not found based on associations with genomic data. These results suggest that to better understand the cancer resistance and move toward personalized medicine, it is essential to consider signaling network dynamics that cannot be inferred from static genotypes.",
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Eduati, F, Doldàn-Martelli, V, Klinger, B, Cokelaer, T, Sieber, A, Kogera, F, Dorel, M, Garnett, MJ, Blüthgen, N & Saez-Rodriguez, J 2017, 'Drug resistance mechanisms in colorectal cancer dissected with cell type-specific dynamic logic models' Cancer Research, vol. 77, nr. 12, blz. 3364-3375. DOI: 10.1158/0008-5472.CAN-17-0078

Drug resistance mechanisms in colorectal cancer dissected with cell type-specific dynamic logic models. / Eduati, F.; Doldàn-Martelli, V.; Klinger, B.; Cokelaer, T.; Sieber, A.; Kogera, F.; Dorel, M.; Garnett, M.J.; Blüthgen, N.; Saez-Rodriguez, J.

In: Cancer Research, Vol. 77, Nr. 12, 15.06.2017, blz. 3364-3375.

Onderzoeksoutput: Bijdrage aan tijdschriftTijdschriftartikelAcademicpeer review

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Eduati F, Doldàn-Martelli V, Klinger B, Cokelaer T, Sieber A, Kogera F et al. Drug resistance mechanisms in colorectal cancer dissected with cell type-specific dynamic logic models. Cancer Research. 2017 jun 15;77(12):3364-3375. Beschikbaar vanaf, DOI: 10.1158/0008-5472.CAN-17-0078