An Analysis of Drug Resistance Mechanisms in Plasmodium vivax Malaria and ERα-Positive Breast Cancer and Their Implications for the Prevention Drug Resistance in Future Therapeutic Development

Abstract

Drug resistance is currently one of the most critical health concerns. While the exact mechanisms of drug resistance remain unknown, certain aspects of it can be revealed by studying drug resistance from two perspectives: the microbe and the human cell. Two diseases that are notoriously difficult to treat due to the development of resistance mechanisms are malaria and estrogen receptor α (ERα)-positive breast cancer. The malaria parasite of the genus Plasmodium has developed several genetic mutations which allow it to circumvent the therapeutic actions of current antimalarials, indicating the importance of identifying novel drug targets. Plasmodium vivax Equilibrative Nucleoside Transporter 1 (PvENT1) has been identified as a potential drug target, but the potential of resistant mechanisms emerging to PvENT1 inhibitors through genetic mutations has yet to be sufficiently determined. Characterization of PvENT1 single nucleotide polymorphisms (SNPs) showed that overall, the transporter’s function remains unchanged, indicating the potential success of PvENT1 inhibitors. Additionally, the development of endocrine therapy resistance offers a different perspective of drug resistance. It is found to occur in part due to the molecular cross-talk between the ERα and growth factor signaling pathways, such as the mammalian Target of Rapamycin (mTOR) pathway. Combination treatments using endocrine therapy and mTOR inhibitors have been proposed to prevent the emergence of endocrine therapy resistance. The discovery of a direct link between the ERα and mTOR pathways, the binding of ERα to regulatory associated protein of mTOR (raptor), provides a new, viable target for mTOR inhibitors administered in combination with endocrine therapy. The findings presented in this work are therefore important steps in the ongoing effort to successfully identify new treatments for these two diseases. Moreover, this work expounds 3 upon the importance of furthering scientific understanding of drug resistance mechanisms, and of identifying novel treatments that would combat and prevent the development of drug resistance.