Multi-oncogene targeting in cancer therapy: A miRNA-driven pharmacological approach

MicroRNAs/miRNAs are known epigenetic regulators that function as rheostats to regulate gene expression in cells. miRNA can simultaneously target multiple genes, thus profoundly impacting cellular physiology. Cancer is one of the most complex diseases. It often involves the interplay of various genes, making anti-cancer therapies targeting a single gene less effective. It leads to the development of resistance to treatment over time, thus limiting long-term beneficial outcomes. In contrast, the ability of miRNAs to target multiple genes simultaneously might make them suitable as effective anti-cancer drugs. Many of these genes can exhibit diverse functions, including oncogenes, transcription factors, and cell signaling mediators. In this article, we review the known roles of miRNAs, their multi-targeting capabilities, and their potential to serve as anti-cancer therapeutics. To demonstrate this potential, we have examined several cancers that are particularly challenging to treat, such as Non-Small Cell Lung Cancer (NSCLC), Melanoma, and Triple-Negative Breast Cancer (TNBC). We identified miRNAs that are capable of simultaneously targeting multiple tumor-promoting genes. These miRNA candidates could serve as potential therapeutics for cancers with a multigenic origin. In addition, miRNA also has the potential to serve as prognostic and diagnostic markers. We discussed recent developments in targeting signaling pathways and immune checkpoint inhibitors using miRNAs and modulation of the tumor microenvironment by delivering base-modified miRNA into cells. Thus, we propose that miRNAs can be leveraged as a pharmacological intervention in multigenic cancers.