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Repurposing Mercaptopurine Through Collateral Lethality to Treat Cancers with Somatic RB1-NUDT15 Loss
Tao Zhou1,2, Huayun Yan2, Dandan Yin2
1Department of Laboratory Medicine/Research Centre of Clinical Laboratory Medicine West China Hospital Sichuan University Chengdu Sichuan China.
Abstract:
Somatic retinoblastoma 1 (RB1) 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 (NUDT15) and RB1 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 RB1 and NUDT15 were commonly observed (14 out of 21). Due to the contribution of NUDT15 deficiency to thiopurine-induced toxicity, exploiting a vulnerability conferred by RB1-NUDT15 loss raised the possibility of repurposing thiopurine (e.g., mercaptopurine) for precise therapeutics. A positive relationship between RB1/NUDT15 ploidy score and mercaptopurine drug sensitivity was found in 543 cancer cell lines. Experimentally, knocking-down NUDT15 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.
Insights
Loss of retinoblastoma 1 (RB1) and nudix hydrolase 15 (NUDT15) in tumors creates a vulnerability. This finding supports repurposing mercaptopurine for precise cancer therapy in patients with RB1-deficient tumors.
Area of Science:
- Oncology
- Cancer Genetics
- Pharmacology
Background:
- Somatic retinoblastoma 1 (RB1) loss is common in treatment-refractory cancers like castration-resistant prostate cancer (CRPC).
- RB1 is not a directly druggable target, necessitating alternative therapeutic strategies.
- Nudix hydrolase 15 (NUDT15) deficiency is linked to thiopurine toxicity.
Purpose of the Study:
- To investigate the link between RB1 and NUDT15 in cancer development and treatment.
- To explore the potential of repurposing thiopurines, like mercaptopurine, for RB1-deficient tumors.
- To identify vulnerabilities conferred by the co-loss of RB1 and NUDT15.
Main Methods:
- Analysis of gene co-deletion and co-silencing patterns.
- Correlation analysis of RB1 and NUDT15 expression at bulk and single-cell levels.
- Assessment of mercaptopurine sensitivity in cancer cell lines and xenograft models.
Main Results:
- Common co-loss of RB1 and NUDT15 was observed in clinical CRPC samples.
- A positive correlation between RB1/NUDT15 ploidy score and mercaptopurine sensitivity was found in 543 cancer cell lines.
- NUDT15 knockdown sensitized cancer cells to mercaptopurine by inhibiting cell cycle and increasing apoptosis, without causing leucopenia in vivo.
Conclusions:
- The co-loss of RB1 and NUDT15 presents a targetable vulnerability for precise mercaptopurine therapy.
- Drug repurposing of thiopurines, like mercaptopurine, can be leveraged for stratified patient cohorts with RB1-deficient tumors.
- This study elucidates the molecular basis for collateral lethality and precise therapeutic strategies in oncology.
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