AI Article Synopsis
- Enzalutamide is an androgen receptor pathway inhibitor that can extend survival in metastatic prostate cancer patients, but resistance to it often develops due to unclear mechanisms.
- Kinesin family member 15 (KIF15) is shown to enhance AR signaling, contributing to enzalutamide resistance by preventing the degradation of AR proteins through its interaction with a specific enzyme.
- Targeting KIF15 alongside enzalutamide may offer a promising new therapeutic strategy to combat prostate cancer that has developed resistance to treatment.
Article Abstract
The new generation androgen receptor (AR) pathway inhibitor enzalutamide can prolong the survival of patients with metastatic prostate cancer. However, resistance to enzalutamide inevitably develops in these patients, and the underlying mechanisms of this resistance are not fully defined. Here we demonstrate that the kinesin family member 15 (KIF15) contributes to enzalutamide resistance by enhancing the AR signaling in prostate cancer cells. KIF15 directly bound the N-terminus of AR/AR-V7 and prevented AR/AR-V7 proteins from degradation by increasing the protein association of ubiquitin-specific protease 14 (USP14) with AR/AR-V7. In turn, the transcriptionally active AR stimulated KIF15 expression. KIF15 inhibitors alone or in combination with enzalutamide significantly suppressed enzalutamide-resistant prostate cancer cell growth and xenograft progression. These findings highlight a key role of KIF15 in enabling prostate cancer cells to develop therapy resistance to enzalutamide and rationalize KIF15 as a potential therapeutic target. SIGNIFICANCE: These findings demonstrate how reciprocal activation between KIF15 and AR contributes to enzalutamide resistance in prostate cancer and highlights cotargeting KIF15 and AR as a therapeutic strategy for these tumors.
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| http://dx.doi.org/10.1158/0008-5472.CAN-20-1965 | DOI Listing |
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