Project description:The goal of the CTD2 Pancancer Drug Activity DREAM Challenge is to foster the development and benchmarking of algorithms to predict targets of chemotherapeutic compounds from post-treatment transcriptional data. The drug perturbational profiles on 11 cell lines for 32 kinase inhibitors with well-established targets were provided to challenge participants, without revealing the identity of the drugs. These profiles were used to predict the drug-targets of the 32 anonymized drugs using publically available datasets for training.
Project description:DARPP-32 expression was reduced in oestrogen receptor positive luminal B breast cancer cells (T47D) using siRNA and control and DARPP-32 knockdown cells were subject to stimulation with estradiol17β (E2) or inhibition of protein kinase A (PKA) with PKA inhibitor fragment (6-22) amide prior to RNA sequencing. A bioinformatics pipeline of Trim Galore, Kallisto, DESeq2 and Qiagen Ingenuity Pathway Analysis was used for pathway analysis.
Project description:U-2 OS (human osteosarcoma cell line) were treated with ZM447439 (an aurora kinase inhibitor), SB202190 (a p38 inhibitor) or ZM447439+SB202190 and resulting changes in gene expression were profiled.
Project description:Background and aims: Synthetic cyclin-dependent kinase (CDK) 4/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy. Approach and results: Loss of all Rb family members in transformation related protein 53 (Trp53)-/- mouse liver resulted in liver tumor reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into multiple liver tumor cell lines induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an I kappa B kinase (IKK)β inhibitor Bay 11-7082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/β phosphorylation and NF-κB activation. Combination therapy using palbociclib with Bay 11-7082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK-NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers. Conclusions: In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1-intact cancers including HCC when combined with an appropriate kinase inhibitor.