NDLI: Variant allele frequency enrichment analysis in vitro reveals sonic hedgehog pathway to impede sustained temozolomide response in GBM

Content Provider	PubMed Central
Author	Biswas, Nidhan K. Chandra, Vikas Sarkar-roy, Neeta Das, Tapojyoti Bhattacharya, Rabindra N. Tripathy, Laxmi N. Basu, Sunandan K. Kumar, Shantanu Das, Subrata Chatterjee, Ankita Mukherjee, Ankur Basu, Pryiadarshi Maitra, Arindam Chattopadhyay, Ansuman Basu, Analabha Dhara, Surajit
Copyright Year	2015
Abstract	Neoplastic cells of Glioblastoma multiforme (GBM) may or may not show sustained response to temozolomide (TMZ) chemotherapy. We hypothesize that TMZ chemotherapy response in GBM is predetermined in its neoplastic clones via a specific set of mutations that alter relevant pathways. We describe exome-wide enrichment of variant allele frequencies (VAFs) in neurospheres displaying contrasting phenotypes of sustained versus reversible TMZ-responses in vitro. Enrichment of VAFs was found on genes ST5, RP6KA1 and PRKDC in cells showing sustained TMZ-effect whereas on genes FREM2, AASDH and STK36, in cells showing reversible TMZ-effect. Ingenuity pathway analysis (IPA) revealed that these genes alter cell-cycle, G2/M-checkpoint-regulation and NHEJ pathways in sustained TMZ-effect cells whereas the lysine-II&V/phenylalanine degradation and sonic hedgehog (Hh) pathways in reversible TMZ-effect cells. Next, we validated the likely involvement of the Hh-pathway in TMZ-response on additional GBM neurospheres as well as on GBM patients, by extracting RNA-sequencing-based gene expression data from the TCGA-GBM database. Finally, we demonstrated TMZ-sensitization of a TMZ non-responder neurosphere in vitro by treating them with the FDA-approved pharmacological Hh-pathway inhibitor vismodegib. Altogether, our results indicate that the Hh-pathway impedes sustained TMZ-response in GBM and could be a potential therapeutic target to enhance TMZ-response in this malignancy.
Related Links	http://dx.doi.org/10.1038/srep07915
Starting Page	7915
File Format	PDF
ISSN	20452322
e-ISSN	20452322
Journal	Scientific Reports
Volume Number	5
Language	English
Publisher	Nature Publishing Group
Publisher Date	2015-01-01
Access Restriction	Open
Rights Holder	Nature Publishing Group
Subject Keyword	Science and technology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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