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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.

SUBMITTER: Ozturk S

PROVIDER: S-EPMC7666085 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Leflunomide triggers synthetic lethality in PTEN-deficient prostate cancer.

Ozturk Sait S Mathur Deepti D Zhou Royce W RW Mulholland David D Parsons Ramon R

Prostate cancer and prostatic diseases 20200713 4

<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>Here, we demonstrate that PTEN-deficient prostate cancer cell ...[more]

PMID: 32661432

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