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A computational study of hedgehog signalling involved in basal cell carcinoma reveals the potential and limitation of combination therapy
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland;Swiss Inst Bioinformat, Switzerland. (Ctr Biomat Chem;Ctr Ecol & Evolut Microbial Model Syst)ORCID iD: 0000-0002-6469-0296
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Univ Svizzera Italiana, Switzerland;Swiss Inst Bioinformat, Switzerland. (Ctr Biomat Chem;Ctr Ecol & Evolut Microbial Model Syst)
(Ctr Biomat Chem;CCBG;BMC)ORCID iD: 0000-0001-8696-3104
2018 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 18, article id 569Article in journal (Refereed) Published
Abstract [en]

Background: The smoothened (SMO) receptor is an essential component of the Sonic hedgehog (SHH) signalling, which is associated with the development of skin basal cell carcinoma (BCC). SMO inhibitors are indicated for BCC patients when surgical treatment or radiation therapy are not possible. Unfortunately, SMO inhibitors are not always well tolerated due to severe side effects, and their therapeutical success is limited by resistance mutations. Methods: We investigated how common are resistance-causing mutations in two genomic databases which are not linked to BCC or other cancers, namely 1000 Genomes and ExAC. To examine the potential for combination therapy or other treatments, we further performed knowledge-based simulations of SHH signalling, in the presence or absence of SMO and PI3K/Akt inhibitors. Results: The database analysis revealed that of 18 known mutations associated with Vismodegib-resistance, three were identified in the databases. Treatment of individuals carrying such mutations is thus liable to fail a priori. Analysis of the simulations suggested that a combined inhibition of SMO and the PI3K/Akt signalling pathway may provide an effective reduction in tumour proliferation. However, the inhibition dosage of SMO and PI3K/Akt depended on the activity of phosphodiesterases (PDEs). Under high PDEs activities, SMO became the most important control node of the network. By applying PDEs inhibition, the control potential of SMO decreased and P13K appeared as a significant factor in controlling tumour proliferation. Conclusions: Our systems biology approach employs knowledge-based computer simulations to help interpret the large amount of data available in public databases, and provides application-oriented solutions for improved cancer resistance treatments.

Place, publisher, year, edition, pages
BioMed Central, 2018. Vol. 18, article id 569
National Category
Cancer and Oncology Bioinformatics and Systems Biology
Research subject
Natural Science, Biomedical Sciences
Identifiers
URN: urn:nbn:se:lnu:diva-76627DOI: 10.1186/s12885-018-4451-1ISI: 000432706500002PubMedID: 29776351OAI: oai:DiVA.org:lnu-76627DiVA, id: diva2:1230415
Funder
Swedish Cancer Society, CAN 2015/387Available from: 2018-07-03 Created: 2018-07-03 Last updated: 2018-07-12Bibliographically approved

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Buetti-Dinh, Antoine

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