BMS-690514

According to reports, MAP3K14 is considered an oncogene and is aberrantly expressed in various types of tumor cells. Its abnormal expression is closely associated with the occurrence and progression of various cancers. MAP3K14 also plays a significant role in the development of non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma and its connection to tumor stem cells. The prognostic value of MAP3K14 in HCC, as well as its potential functions and roles, requires further elucidation. We evaluated the potential role of MAP3K14 in HCC based on data mining from a range of public databases. The bioinformatics analysis of TCGA, GEO, TIMER, cBioportal, Kaplan-Meier plotter, MethSurv, ENCORI and CellMiner databases was carried out. The expression of MAP3K14 protein in HCC was detected by immunohistochemical method. The mRNA and protein expression levels of MAP3K14 in tumor tissues were higher than those in normal tissues (p < 0.05). The expression of MAP3K14 was correlated with Pathologic T stage (p=0.026), Pathologic stage (p=0.032), Tumor status (p=0.024) and AFP (p=0.002). HCC patients with high expression of MAP3K14 had poor overall survival (OS), progression free survival (PFS) and recurrence free survival (RFS). Multivariate Cox regression analysis showed that the Pathologic stage (p < 0.001) and MAP3K14 expression levels (p < 0.05) is an independent prognostic factor affecting the survival of patients with liver cancer. GO/KEGG analysis suggested that key biological processes (PI3K-Akt signaling pathway) may be the mechanism promoting HCC development. In addition, MAP3K14 was significantly correlated with the infiltrating levels of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells (p < 0.05). MAP3K14 is up-regulated in HCC and is closely related to the prognosis of HCC patients. MAP3K14 may serve as a potential biomarker for poor prognosis of HCC.

Colorectal cancer possesses the third highest diagnostic rate and is the second leading cause of cancer death in the USA as reported by NIH. Epidermal Growth Factor Receptor (EGFR), a transmembrane protein, participates in PLC gamma-1, RAS-RAF-MEK-MAPKs, phosphatidylinositol-3 kinase, Akt pathways and plays a key role in normal functioning of cell division, cell differentiation, apoptosis and migration. This protein is found to be overexpressed in more than 60% of the colorectal cancers. Overexpressed EGFR advances the tumorigenic properties through cell cycle dysregulation and activates signaling pathways linked to cancer such as WNT/β-catenin, transforming growth factor β (TGF-β) and phosphoinositide-3-kinase (PI3K). Inhibiting the overexpressed EGFR protein has been proposed for the treatment and many inhibitors have been reported suppressing the activity of EGFR. However, patients in malignant state of cancer show resistance to those inhibitors, which open a wide space to research for the discovery of novel inhibitors. The present study employed Molecular Docking and Virtual Screening to find novel inhibitors with high affinity against EGFR. Molecular docking of existing inhibitors resulted in the compound titled as BGB-283 (PubChem CID-89670174) having the highest score, which was subjected to similarity search to retrieve the drugs with similar structure. The virtual screening concluded a compound SCHEMBL18435602 (PubChem CID-126517400) which revealed a better affinity with the target protein. A comparative study of both the compounds showed equivalent pharmacokinetic properties. These identified drugs have a high potential to act as EGFR inhibitors and can show promising results in the research of colorectal cancer.