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

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Nucleoside analogs are crucial in treating hematologic malignancies and solid tumors.
• Therapeutic resistance to nucleoside analogs often leads to cancer relapse and mortality.

Purpose of the Study:

• To review mechanisms of nucleoside analog resistance.
• To highlight strategies for overcoming resistance and enhancing therapy efficacy.

Main Methods:

• Literature review integrating recent advances on nucleoside analog resistance.
• Analysis of biological barriers affecting nucleoside analog activity.
• Exploration of small-molecule inhibitors targeting resistance mechanisms.

Main Results:

• Resistance arises from multiple biological barriers: cellular uptake, intracellular activation, nucleotide pool balance, genome surveillance, and mitochondrial stress.
• Alterations at each level contribute significantly to treatment failure.
• Small-molecule inhibitors can exploit these vulnerabilities to enhance nucleoside analog efficacy.

Conclusions:

• Developing small molecule inhibitors is essential for overcoming nucleoside analog resistance.
• Combination therapies targeting resistance mechanisms can improve patient outcomes.
• Restoring apoptotic competence is key to enhancing nucleoside analog-based cancer therapies.