Adaptive Rewiring of Nucleotide Metabolism in Therapeutic Resistance
- 1Department of Medical Oncology, Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
- 2Key Laboratory of Chinese Medicine Resource and Compound Prescription, Ministry of Education, Hubei University of Chinese Medicine, Wuhan 430065, China
- 3Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Abstract
Therapeutic resistance remains a major barrier to durable cancer control and is increasingly recognized as a dynamic process shaped not only by genetic evolution but also by metabolic adaptation. Nucleotide metabolism is uniquely positioned at this interface, supporting DNA and RNA synthesis while also regulating signaling, energy homeostasis, redox balance, genome maintenance, and cellular stress responses. In this Review, we examine emerging evidence that cancer cells in solid tumors adapt nucleotide metabolism in response to therapeutic pressure through coordinated remodeling of de novo biosynthesis, nucleotide salvage, metabolite transport, and pathway-specific feedback mechanisms. We discuss how cytotoxic chemotherapy, targeted therapies, immunotherapies, and radiation impose distinct but convergent pressures on nucleotide homeostasis and how restoration or redistribution of nucleotide pools can promote survival, DNA repair, persistent oncogenic signaling, and immune evasion. We further highlight the reciprocal relationship between oncogenic signaling and nucleotide metabolism, as well as the contribution of tumor suppressor loss and the tumor microenvironment to context-specific metabolic dependencies. Rather than functioning only as a biosynthetic requirement of proliferating cells, nucleotide metabolism emerges as a flexible stress-response network that can facilitate adaptation to cancer therapy. Defining the mechanisms that maintain nucleotide balance in resistant tumors may reveal therapeutically actionable dependencies and inform rational combination strategies designed to prevent or overcome treatment resistance.
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BibTeX
@article{dayanc2026adaptive,
title = {{Adaptive Rewiring of Nucleotide Metabolism in Therapeutic Resistance}},
author = {Bengisu Dayanc and Ganfei Xu and Xiaoshu Zhou and Jinpeng Chen and Noah Mueller and Harsimran Kaur and Breanna Pham and Satoshi Yoda and Jaime L. Schneider},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18213498},
url = {https://www.mdpi.com/2072-6694/18/21/3498},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Adaptive Rewiring of Nucleotide Metabolism in Therapeutic Resistance
AU - Bengisu Dayanc
AU - Ganfei Xu
AU - Xiaoshu Zhou
AU - Jinpeng Chen
AU - Noah Mueller
AU - Harsimran Kaur
AU - Breanna Pham
AU - Satoshi Yoda
AU - Jaime L. Schneider
PY - 2026
DA - 2026/10/30
JO - Cancers
DO - 10.3390/cancers18213498
UR - https://www.mdpi.com/2072-6694/18/21/3498
AB - Therapeutic resistance remains a major barrier to durable cancer control and is increasingly recognized as a dynamic process shaped not only by genetic evolution but also by metabolic adaptation. Nucleotide metabolism is uniquely positioned at this interface, supporting DNA and RNA synthesis while also regulating signaling, energy homeostasis, redox balance, genome maintenance, and cellular stress responses. In this Review, we examine emerging evidence that cancer cells in solid tumors adapt nucleotide metabolism in response to therapeutic pressure through coordinated remodeling of de novo biosynthesis, nucleotide salvage, metabolite transport, and pathway-specific feedback mechanisms. We discuss how cytotoxic chemotherapy, targeted therapies, immunotherapies, and radiation impose distinct but convergent pressures on nucleotide homeostasis and how restoration or redistribution of nucleotide pools can promote survival, DNA repair, persistent oncogenic signaling, and immune evasion. We further highlight the reciprocal relationship between oncogenic signaling and nucleotide metabolism, as well as the contribution of tumor suppressor loss and the tumor microenvironment to context-specific metabolic dependencies. Rather than functioning only as a biosynthetic requirement of proliferating cells, nucleotide metabolism emerges as a flexible stress-response network that can facilitate adaptation to cancer therapy. Defining the mechanisms that maintain nucleotide balance in resistant tumors may reveal therapeutically actionable dependencies and inform rational combination strategies designed to prevent or overcome treatment resistance.
SN - 2072-6694
ER -