Abstract
BackgroundThe 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.MethodsWe 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.ResultsThe 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 PI3K appeared as a significant factor in controlling tumour proliferation.ConclusionsOur 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.
Highlights
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)
Inhibitors such as vismodegib [3] (Erivedgeo, FDA-approved in 2012) and sonidegib [4] (Odozmoo, FDA-approved in 2015) that block SMO are available [5], resistance mutations develop after a period of few months thereby limiting the efficacy of those drugs [6]
We further searched for the presence of resistance mutations in two genomic databases that are not linked to BCC or any other cancer, namely 1000 Genomes and Exome Aggregation Consortium (ExAC)
Summary
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). Amino acid mutations in SMO that lead to an unrestrained receptor activity are called activating mutations [2] Inhibitors such as vismodegib [3] (Erivedgeo , FDA-approved in 2012) and sonidegib [4] (Odozmoo , FDA-approved in 2015) that block SMO are available [5], resistance mutations develop after a period of few months thereby limiting the efficacy of those drugs [6]. Tumours can reinforce an alternative signalling route as a response to the blockage of the main signal transduction path This mechanism of resistance allows cancers to sustain cancerdriving processes such as tumour proliferation despite therapy [7, 8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
