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Published on: June 26, 2019
PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate
Alice Matheux1,2, Matthieu Gassiot1, Gaëlle Fromont3
1IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, ICM, F-34298 Montpellier, France.
Abstract:
Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor level. Here, we studied the role of PXR (Pregnane X Receptor), a master regulator of metabolism, in the resistance to KIs in a prostate cancer setting. We confirmed that PXR is expressed in prostate tumors and is more frequently detected in advanced forms of the disease. We showed that stable expression of PXR in 22Rv1 prostate cancer cells conferred a resistance to dasatinib and a higher sensitivity to erlotinib, dabrafenib, and afatinib. Higher sensitivity to afatinib was due to a ~ 2-fold increase in its intracellular accumulation and involved the SLC16A1 transporter as its pharmacological inhibition by BAY-8002 suppressed sensitization of 22Rv1 cells to afatinib and was accompanied with reduced intracellular concentration of the drug. We found that PXR could bind to the SLC16A1 promoter and induced its transcription in the presence of PXR agonists. Together, our results suggest that PXR could be a biomarker of response to kinase inhibitors in castration-resistant prostate cancers.
Insights
Pregnane X Receptor (PXR) influences treatment response in prostate cancer. PXR expression may predict effectiveness of kinase inhibitors in castration-resistant prostate cancer.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Castration resistance is a major challenge in metastatic prostate cancer treatment.
- Kinase inhibitors (KIs) show promise but face resistance due to extensive metabolism.
- The Pregnane X Receptor (PXR) regulates drug metabolism and may impact KI resistance.
Purpose of the Study:
- To investigate the role of PXR in mediating resistance to kinase inhibitors in prostate cancer.
- To determine if PXR expression correlates with disease progression and response to KIs.
Main Methods:
- Studied PXR expression in prostate tumors, correlating it with disease stage.
- Expressed PXR in 22Rv1 prostate cancer cells to assess its impact on KI sensitivity.
- Investigated the role of the SLC16A1 transporter in PXR-mediated afatinib sensitivity using pharmacological inhibition.
Main Results:
- PXR is expressed in prostate tumors, with higher prevalence in advanced stages.
- PXR expression conferred resistance to dasatinib but increased sensitivity to erlotinib, dabrafenib, and afatinib.
- Afatinib sensitivity was linked to increased intracellular accumulation via the SLC16A1 transporter, which PXR induces transcriptionally.
Conclusions:
- PXR plays a significant role in modulating prostate cancer cell response to various kinase inhibitors.
- PXR may serve as a predictive biomarker for kinase inhibitor efficacy in castration-resistant prostate cancer.
- Targeting PXR or its downstream effectors like SLC16A1 could offer novel therapeutic strategies.
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