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Leflunomide triggers synthetic lethality in PTEN-deficient prostate cancer

Abstract

Background

The loss of PTEN function presents in up to 50% of late-stage prostate cancers, and is therefore a potential target for therapeutics. PTEN-deficient cells depend on de novo pyrimidine synthesis, a feature that can present a vulnerability.

Methods

We utilized in vitro growth assays and in vivo xenograft models to test the effect of de novo pyrimidine synthesis inhibition on prostate cell lines.

Results

Here, we demonstrate that PTEN-deficient prostate cancer cell lines are susceptible to inhibition of de novo pyrimidine synthesis by leflunomide. Tumor growth inhibition was observed in vitro and in vivo following leflunomide treatment, and is likely due to an overwhelming accumulation of DNA damage.

Conclusions

Our work highlights that synthetic lethality arises upon the combination of PTEN loss and leflunomide treatment in prostate cancer, and may present a therapeutic opportunity for this patient population.

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Fig. 1: The effect of PTEN loss and leflunomide treatment on prostate cells in vitro.
Fig. 2: Leflunomide treatment on PTEN null prostate cancer xenografts.

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Acknowledgements

We thank all the Parsons’s lab members for their critical input during the planning, execution and reporting phases of the study. Grant Support: Grant support for this work was provided by Prostate Cancer Foundation 2016 PCF Challenge Award 16CHAL14 and National Cancer Institute R35 CA220491.

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Correspondence to Ramon Parsons.

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Conflict of interest

RP is a shareholder of Therapten, Inc., a company focused on using an isoform of PTEN protein as a treatment for disease. The authors declare that they have no conflict of interest.

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Ozturk, S., Mathur, D., Zhou, R.W. et al. Leflunomide triggers synthetic lethality in PTEN-deficient prostate cancer. Prostate Cancer Prostatic Dis 23, 718–723 (2020). https://doi.org/10.1038/s41391-020-0251-1

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