Repurposing Mercaptopurine Through Collateral Lethality to Treat Cancers with Somatic <i>RB1–NUDT15</i> Loss

Somatic retinoblastoma 1 (<i>RB1</i>) loss is prevalent across different cancer types and is enriched in treatment-refractory tumors, such as castration-resistant prostate cancer (CRPC) and small-cell lung cancer, but cannot be considered as a direct druggable target. In this study, we revealed that the close proximity of nudix hydrolase 15 (<i>NUDT15</i>) and <i>RB1</i> may result in their common somatic codeletion or epigenomic cosilencing in different cancer types and subsequent significant positive correlations of their expressions at the bulk transcriptional and single-cell levels. With clinical CRPC samples, co-loss of <i>RB1</i> and <i>NUDT15</i> were commonly observed (14 out of 21). Due to the contribution of <i>NUDT15</i> deficiency to thiopurine-induced toxicity, exploiting a vulnerability conferred by <i>RB1-NUDT15</i> loss raised the possibility of repurposing thiopurine (e.g., mercaptopurine) for precise therapeutics. A positive relationship between <i>RB1</i>/<i>NUDT15</i> ploidy score and mercaptopurine drug sensitivity was found in 543 cancer cell lines. Experimentally, knocking-down <i>NUDT15</i> sensitizes the cancer cell lines to mercaptopurine treatment by inhibiting cell cycle progression and increasing apoptosis, but does not induce mercaptopurine-related leucopenia in xenograft model. Our study elucidates the molecular basis for precise mercaptopurine therapy in RB1-deficient tumors and demonstrates how leveraging collateral lethality alongside drug repurposing uncovers targetable vulnerabilities in stratified patient cohorts.

Authors

Institutions

Publication Details

Journal
MedComm
Published
2025-09-01
DOI
https://doi.org/10.1002/mco2.70361
Citations
1
Primary Topic
Epigenetics and DNA Methylation
Type
article
Field-Weighted Citation Impact
0.81

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Repurposing Mercaptopurine Through Collateral Lethality to Treat Cancers with Somatic RB1–NUDT15 Loss

Weihan Zhang, Xiaoxi Lu, S. Li, Huayun Yan et al.
1 citations
MedComm
Epigenetics and DNA Methylation
0.81
article

Repurposing Mercaptopurine Through Collateral Lethality to Treat Cancers with Somatic RB1–NUDT15 Loss

Weihan Zhang, Xiaoxi Lu, S. Li, Huayun Yan, Lili Jiang, Dandan Yin, Hai‐Ning Chen, Bei Cai, Huancheng Fu, Zichen Zhao, Yunying Shi, Wei Zhang, Yan Zhang, Heng Xu, Lanlan Wang, Yang Shu, Tao Zhou, Yun Deng, Yiqi Deng, Zhaoqian Liu, Yangjuan Bai, Bo Liu
article en
1 citations

Abstract

Somatic retinoblastoma 1 (<i>RB1</i>) loss is prevalent across different cancer types and is enriched in treatment-refractory tumors, such as castration-resistant prostate cancer (CRPC) and small-cell lung cancer, but cannot be considered as a direct druggable target. In this study, we revealed that the close proximity of nudix hydrolase 15 (<i>NUDT15</i>) and <i>RB1</i> may result in their common somatic codeletion or epigenomic cosilencing in different cancer types and subsequent significant positive correlations of their expressions at the bulk transcriptional and single-cell levels. With clinical CRPC samples, co-loss of <i>RB1</i> and <i>NUDT15</i> were commonly observed (14 out of 21). Due to the contribution of <i>NUDT15</i> deficiency to thiopurine-induced toxicity, exploiting a vulnerability conferred by <i>RB1-NUDT15</i> loss raised the possibility of repurposing thiopurine (e.g., mercaptopurine) for precise therapeutics. A positive relationship between <i>RB1</i>/<i>NUDT15</i> ploidy score and mercaptopurine drug sensitivity was found in 543 cancer cell lines. Experimentally, knocking-down <i>NUDT15</i> sensitizes the cancer cell lines to mercaptopurine treatment by inhibiting cell cycle progression and increasing apoptosis, but does not induce mercaptopurine-related leucopenia in xenograft model. Our study elucidates the molecular basis for precise mercaptopurine therapy in RB1-deficient tumors and demonstrates how leveraging collateral lethality alongside drug repurposing uncovers targetable vulnerabilities in stratified patient cohorts.

MedCommVol. 6(9)
Central South University (CN), Sichuan University (CN), West China Second University Hospital of Sichuan University (CN), West China Hospital of Sichuan University (CN), Health and Family Planning Commission of Sichuan Province (CN), Sichuan Cancer Hospital (CN), PharmacoGenetics (China) (CN), Xiangya Hospital Central South University (CN), State Key Laboratory of Biotherapy
National Natural Science Foundation of China, Sichuan University, National Key Research and Development Program of China, West China Hospital, Sichuan University
Openalex Percentile: Top 24%
Epigenetics and DNA Methylation
0.81
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.