Nuclear Receptors and Stress Response Pathways Associated with the Development of Oral Mucositis Induced by Antineoplastic Agents

Abstract

Oral mucositis (OM) is one of the common adverse events associated with cancer treatment that decreases the quality of life and affects treatment outcomes. However, the medications used to manage OM are generally only palliative, and our knowledge of the syndrome is limited. The etiology of the syndrome is thought to be complex and multifactorial. We investigated the trends and characteristics of OM and estimated molecular initiating events (MIEs) associated with the development of the syndrome using the FDA Adverse Event Reporting System. The study of trends and characteristics suggested that OM is significantly more likely to occur in females and nonelderly patients and is likely to be induced by protein kinase inhibitors such as afatinib and everolimus. Next, we used Toxicity Predictor, an in-house quantitative structure-activity relationship system, to estimate OM-associated MIEs. The results revealed that the agonist activity of the human pregnane X receptor, thyroid-stimulating hormone-releasing hormone receptor, and androgen receptor may be associated with OM development. Our study findings are expected to help avoid the risk of OM induction during the drug discovery process and clinical use of antineoplastic agents.

Keywords: antineoplastic agent; molecular initiating event; oral mucositis.

Figure 1

Flowchart of the creation of a data table for analysis. DRUG: drug information, REAC: adverse reaction information, and DEMO: patient demographic information. Duplicate data in the DRUG, REAC, and DEMO tables were deleted and combined using primary IDs.

Figure 2

The number of reports with 17 preferred terms related to stomatitis, defined using high-level terms of MedDRA.

Figure 3

Correlation between antineoplastic agents and stomatitis. The x-axis shows lnROR; the y-axis shows the ordinary logarithm of the reciprocal p-value of Fisher’s exact test (−log [p-Value]). The reporting odds ratio (ROR) was calculated from cross-tabulation tables. The dotted line on the x-axis indicates lnROR = 0; the dotted line on the y-axis indicates p = 0.5. The colors in the plots indicate the ordinary logarithm of the total number of adverse events reported for each drug.

Figure 4

MIEs associated with OM. The vertical axis shows lnROR and the horizontal axis shows MIE activity or not: MIE activity values < 0.5 indicate no activity with a predictive label of “inactive”, whereas MIE activity values > 0.5 indicate activity with a predictive label of “active”. The green line shows the mean value of lnROR and its 95% confidence interval. Each plot represents the antineoplastic agent under analysis. PXR, human pregnane X receptor; TRHR, thyrotropin-releasing hormone receptor; ARlbd, androgen receptor ligand-binding domain; ARant, androgen receptor with antagonist.