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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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Epigenetic Biomarkers for Predicting Nucleoside Analog Drug Response and Resistance in Cancer

John Kaszycki1, Jackson C Lin1, Minji Kim1

  • 1The Division of Medicinal Chemistry, Department of Pharmaceutical Science, School of Pharmacy, The University of Connecticut, Storrs, CT 06269, USA.

Biomolecules
|May 4, 2026
PubMed

Insights

Epigenetic biomarkers can predict patient response to nucleoside analogs (NAs) in cancer therapy. Standardizing these biomarkers will enable personalized NA treatments, improving long-term effectiveness and overcoming resistance.

Area of Science:

  • Oncology
  • Epigenetics
  • Pharmacogenomics

Background:

  • Nucleoside analogs (NAs) are crucial in cancer therapy but face challenges with patient response variability and resistance.
  • Epigenetic factors like DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) significantly influence NA sensitivity and resistance.

Purpose of the Study:

  • To review the epigenetic control mechanisms governing responses to cytotoxic and epigenetic nucleoside analogs.
  • To discuss predictive epigenetic biomarkers, including promoter methylation of hENT1 and dCK, histone modifications, and ncRNA signatures.
  • To assess multi-omic integration strategies and advancements in detection technologies for clinical translation.

Main Methods:

  • Literature review of epigenetic regulation in nucleoside analog therapy.
  • Analysis of predictive biomarkers for NA sensitivity and resistance.
  • Evaluation of high-resolution sequencing, single-cell profiling, and liquid biopsy techniques.
  • Discussion of multi-omic data integration.

Main Results:

  • Epigenetic modifications play a critical role in determining patient outcomes with nucleoside analog therapy.
  • Biomarkers such as hENT1 and dCK promoter methylation, histone modifications, and ncRNA profiles show potential for predicting response.
  • Advancements in detection technologies offer improved resolution and personalized profiling.

Conclusions:

  • Epigenetic biomarkers hold significant promise for stratifying patients in clinical trials and personalizing nucleoside analog treatments.
  • Standardization of biomarker detection methods and development of integrated biomarker panels are essential for clinical translation.
  • Future directions include real-time monitoring, combination strategies, and biomarker-guided trial designs to enhance NA therapy precision and durability.
Keywords:
DNA methylationbiomarkerschemoresistanceepigeneticshistone modificationnucleoside analogsprecision oncology

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