Integrated transcriptome analysis and in silico investigations identify KHDRBS3 to target with steroidal lactone in...

Breast cancer is regarded as a heterogeneous disease with multiple different subtypes. The Basal-like subtype has the worst prognosis with a potential to resist and recur. Within the tumor, cancer stem cells have the ability to persist and also regrow the tumor after treatment. Lack of distinctive molecular markers and understudied drug targetable mechanisms are major hindrances while treating this subtype of patients. In this study, we aimed to study the genes representing Basal-like properties and also elucidate their association with Paclitaxel resistance and stemness properties via a multimodal bioinformatics approach. Furthermore, evaluate the ability of the screened genes to predict treatment response of patients receiving taxane based therapy. We obtained list of genes upregulated in Basal-like subtype of breast cancer from the TCGA-BRCA project. These genes had the most significant overlap with curated gene signature of embryonal carcinoma. Additionally, from the overlapped list of genes we found that KHDRBS3 gene is present within the Paclitaxel resistance associated gene signature of TNBC cells. Increased levels of KHDRBS3 was associated with a reduced overall survival of patients with basal-like breast cancer. KHDRBS3 also predicted the possibility of not responding to taxane-based therapy. Finally using the computational molecular docking and molecular dynamic simulation over a time period of 60 ns we screened a steroidal lactone i.e. Withaferin A, that showed strong binding affinity towards the active site of KHDRBS3 and also qualified drug-likeness properties essential to be utilized for therapeutic purposes in future.