CP-724714

Drug-induced liver injury (DILI) is a frequent cause of clinical trial failures during drug development. While inhibiting bile salt export pump (BSEP) is a well-documented DILI mechanism, interference with genes related to bile acid (BA) metabolism and transport can further complicate DILI development. Here, the effects of twenty-eight compounds on genes associated with BA metabolism and transport were evaluated, including those with discontinued development or use, boxed warnings, and clean labels for DILI. The study also included rifampicin and omeprazole, pregnane X receptor and aryl hydrocarbon receptor ligands, and four mitogen-activated protein kinase kinase (MEK1/2) inhibitors. BSEP inhibitors with more severe DILI, notably pazopanib and CP-724714, significantly upregulated the expression of 7 alpha-hydroxylase (CYP7A1), independent of small heterodimer partner (SHP) expression. CYP7A1 expression was marginally induced by omeprazole. In contrast, its expression was suppressed by mometasone (10-fold), vinblastine (18-fold), hexachlorophene (2-fold), bosentan (2.1-fold), and rifampin (2-fold). All four MEK1/2 inhibitors that show clinical DILI were not potent BSEP inhibitors but significantly induced CYP7A1 expression, accompanied by a significant SHP gene suppression. Sulfotransferase 2A1 and BSEP were marginally upregulated, but no other genes were altered by the drugs tested. Protein levels of CYP7A1 were increased with the treatment of CYP7A1 inducers and decreased with obeticholic acid, an farnesoid X receptor ligand. CYP7A1 inducers significantly increased bile acid (BA) production in hepatocytes, indicating the overall regulatory effects of BA metabolism. This study demonstrates that CYP7A1 induction via various mechanisms can pose a risk for DILI, independently or in synergy with BSEP inhibition, and it should be evaluated early in drug discovery. SIGNIFICANCE STATEMENT: Kinase inhibitors, pazopanib and CP-724714, inhibit BSEP and induce CYP7A1 expression independent of small heterodimer partner (SHP) expression, leading to increased bile acid (BA) production and demonstrating clinically elevated drug-induced liver toxicity. MEK1/2 inhibitors that show BSEP-independent drug-induced liver injury (DILI) induced the CYP7A1 gene accompanied by SHP suppression. CYP7A1 induction via SHP-dependent or independent mechanisms can pose a risk for DILI, independently or in synergy with BSEP inhibition. Monitoring BA production in hepatocytes can reliably detect the total effects of BA-related gene regulation for de-risking.

The thioredoxin (TMX) system, an important redox system, plays crucial roles in several immune-related diseases. However, there is limited research on the correlation of TMX family gene expression with human pan-cancer prognosis, tumor microenvironment (TME), and immunotherapy.

Based on the integration of several bioinformatics analysis methods, we explored the expression levels and prognostic value of TMX family members in pan-cancer and analyzed their association between TME, immune infiltration, stemness scores, and drug sensitivity. Using KEGG enrichment analysis, we explored the potential signaling pathways of their regulation. Additionally, we conducted a transwell assay to verify the relationship between TMX family gene expression and epithelial-mesenchymal transition (EMT) in liver cancer.

Expression of the TMX family genes was shown to have an obvious intratumoral heterogeneity. In some cancers, TMX family members expression was also been found to correlate with poor prognosis of patients. Furthermore, TMX family genes may serve important roles in TME. The expression of TMX family genes was found to have a strong correlation with the stromal scores, immune scores, DNAss and RNAss in pan-cancer. Specifically, the expression levels of TMX family genes have been found to be associated with immune subtypes of renal clear cell carcinoma and liver hepatocellular carcinoma. High TMX2 expression promote EMT in liver cancer.

The findings of this study may elucidate the biological roles of TMX family genes as potential targets for pan-cancer and also offer valuable insights for further investigating how these genes function in the development and spreading of cancer.