MicroRNAs as Sensitizers of Tyrosine Kinase Inhibitor Resistance in Cancer: Small Molecule Partnerships

Abstract

Tyrosine kinase inhibitors (TKIs) have revolutionized cancer treatments by being less toxic and improving the survival of cancer patients. The greatest challenge to their success is the resistance exhibited by cancer patients. However, the potential of microRNAs (miRNAs) for sensitizing molecules to TKIs has been well recognized, with several reports publishing promising results. Nonetheless, this therapeutic window faces challenges and several often-overlooked limitations. One of the most fundamental challenges is selecting the optimal miRNA candidates for clinical trials, as miRNAs are promiscuous and regulate hundreds of targets. In this review, we describe how miRNAs enhance sensitivity to TKIs across various types of cancer. We highlight several challenges and limitations in achieving a successful collaboration between small molecules (TKIs-miRNAs). Our focus is on proposing a workflow to select the most suitable miRNA candidate, recommending several available bioinformatics tools to develop a successful therapeutic partnership between TKIs and miRNAs. We hope that this initial proposal will provide valuable support for future research.

Keywords: TKIs; cancer; miRNAs; overcome resistance; sensitizing.

Figure 1

Compilation of identified miRNAs as sensitizers of TKIs and their described implications in treatment rescue: induction of apoptosis (miRNAs in green), autophagy (miRNAs in purple), metabolism (miRNAs in orange), cell viability and proliferation (miRNAs in pink).

Figure 2

Current experimental and bioinformatic tools in every step of the workflow to select potential microRNA as therapeutics: (1) screening, (2) target identification, (3) biological function, (4) nodes and master regulators.