# Enhancing the Nucleoside Analog Response with Translational Therapeutic Approaches to Overcome Resistance

## TL;DR

This paper reviews how resistance to nucleoside analogs in cancer treatment can be overcome by combining them with small molecule inhibitors that target resistance mechanisms.

## Contribution

The paper integrates recent advances and highlights therapeutic strategies using small-molecule inhibitors to enhance nucleoside analog efficacy.

## Key findings

- Resistance to nucleoside analogs arises from multiple biological barriers like transport and activation.
- Combining small molecule inhibitors with nucleoside analogs improves treatment outcomes in cancer patients.
- Targeting resistance mechanisms can restore apoptotic competence in cancer cells.

## Abstract

What are the main findings?
The anti-tumor efficacy of nucleoside analogs is dependent on transport, enzymatic activation, nucleotide pools and metabolic responses, which are often aberrant in cancer cells, rendering these chemotherapeutic drugs ineffective.

The anti-tumor efficacy of nucleoside analogs is dependent on transport, enzymatic activation, nucleotide pools and metabolic responses, which are often aberrant in cancer cells, rendering these chemotherapeutic drugs ineffective.

What are the implications of the main findings?
Small molecule inhibitors are being tested/developed to target or downregulate specific mechanisms responsible for resistance to nucleoside analogs. The combination of small molecule inhibitors with nucleoside analogs has enhanced the efficacy of nucleoside analogs and improved patient outcomes.

Small molecule inhibitors are being tested/developed to target or downregulate specific mechanisms responsible for resistance to nucleoside analogs. The combination of small molecule inhibitors with nucleoside analogs has enhanced the efficacy of nucleoside analogs and improved patient outcomes.

Nucleoside analogs remain central to the treatment of hematologic malignancies and solid tumors, yet resistance frequently occurs, contributing to relapse and disease-related mortality. Rather than arising from a single mechanism, effective nucleoside analog activity requires successful navigation of multiple biological barriers, including cellular uptake, intracellular activation, nucleotide pool balance, genome surveillance, and mitochondrial stress responses. This review integrates recent advances describing how alterations at each of these levels contribute to resistance to nucleoside analog therapies. We further highlight emerging therapeutic strategies centered on small-molecule inhibitors that exploit these vulnerabilities to enhance the efficacy of nucleoside analogs. Together, this integrative perspective supports the need for development of small molecule inhibitors and design of combination approaches aimed at restoring apoptotic competence and improving the use of nucleoside analog-based therapies for the treatment of cancer.