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Open AccessArticle

Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments

by Cankut Çubuk 1,2,3, Fatma E. Can 1,4, María Peña-Chilet 1,5,6 and Joaquín Dopazo 1,5,6,7,*
1
Clinical Bioinformatics Area, Fundación Progreso y Salud (FPS), CDCA, Hospital Virgen del Rocio, 41013 Sevilla, Spain
2
Division of Genetics and Epidemiology, Institute of Cancer Research, London SW7 3RP, UK
3
William Harvey Research Institute, Queen Mary University, London EC1M 6BQ, UK
4
Department of Biostatistics, Faculty of Medicine, Izmir Katip Celebi University, 35620 Balatçık, Turkey
5
Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, 41013 Sevilla, Spain
6
Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), 41013 Sevilla, Spain
7
FPS-ELIXIR-ES, Hospital Virgen del Rocío, 41013 Sevilla, Spain
*
Author to whom correspondence should be addressed.
Cells 2020, 9(7), 1579; https://doi.org/10.3390/cells9071579 (registering DOI)
Received: 31 May 2020 / Revised: 22 June 2020 / Accepted: 24 June 2020 / Published: 29 June 2020
Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-specific gene expression activities have over cell functionality and fate. Moreover, we also used the mechanistic modeling framework to simulate the drug interventions and unravel how drug action mechanisms are affected by gender-specific differential gene expression. Interestingly, some cancers have many biological processes significantly affected by these gender-specific differences (e.g., bladder or head and neck carcinomas), while others (e.g., glioblastoma or rectum cancer) are almost insensitive to them. We found that many of these gender-specific differences affect cancer-specific pathways or in physiological signaling pathways, also involved in cancer origin and development. Finally, mechanistic models have the potential to be used for finding alternative therapeutic interventions on the pathways targeted by the drug, which lead to similar results compensating the downstream consequences of gender-specific differences in gene expression. View Full-Text
Keywords: mechanistic models; gene expression; signaling pathways; signal transduction; cancer therapies; drug mechanism of action; gender bias mechanistic models; gene expression; signaling pathways; signal transduction; cancer therapies; drug mechanism of action; gender bias
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Çubuk, C.; Can, F.E.; Peña-Chilet, M.; Dopazo, J. Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments. Cells 2020, 9, 1579.

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