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Specific inhibition of the nuclear exporter exportin-1 attenuates kidney cancer growth
Hiromi I Wettersten1, Yosef Landesman2, Sharon Friedlander2
1Division of Nephrology, Dept. of Internal Medicine, University of California Davis, Davis, California, United States of America.
Purpose:
Despite the advent of FDA-approved therapeutics to a limited number of available targets (kinases and mTOR), PFS of kidney cancer (RCC) has been extended only one to two years due to the development of drug resistance. Here, we evaluate a novel therapeutic for RCC which targets the exportin-1 (XPO1) inhibitor.
Materials And Methods:
RCC cells were treated with the orally available XPO1 inhibitor, KPT-330, and cell viability and Annexin V (apoptosis) assays, and cell cycle analyses were performed to evaluate the efficacy of KPT-330 in two RCC cell lines. Immunoblotting and immunofluorescence analysis were performed to validate mechanisms of XPO1 inhibition. The efficacy and on-target effects of KPT-330 were further analyzed in vivo in RCC xenograft mice, and KPT-330-resistant cells were established to evaluate potential mechanisms of KPT-330 resistance.
Results:
KPT-330 attenuated RCC viability through growth inhibition and apoptosis induction both in vitro and in vivo, a process in which increased nuclear localization of p21 by XPO1 inhibition played a major role. In addition, KPT-330 resistant cells remained sensitive to the currently approved for RCC multi-kinase inhibitors (sunitinib, sorafenib) and mTOR inhibitors (everolimus, temsirolimus), suggesting that these targeted therapeutics would remain useful as second line therapeutics following KPT-330 treatment.
Conclusion:
The orally-available XPO1 inhibitor, KPT-330, represents a novel target for RCC whose in vivo efficacy approaches that of sunitinib. In addition, cells resistant to KPT-330 retain their ability to respond to available RCC therapeutics suggesting a novel approach for treatment in KPT-330-naïve as well as -resistant RCC patients.
Insights
A novel therapy targeting exportin-1 (XPO1) inhibitor KPT-330 shows promise in treating kidney cancer (RCC) by inhibiting growth and inducing apoptosis. Importantly, KPT-330-resistant cells remain responsive to existing RCC treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Limited progress in extending progression-free survival (PFS) for kidney cancer (RCC) despite targeted therapies.
- Drug resistance significantly hinders the efficacy of current FDA-approved treatments for RCC.
- Need for novel therapeutic strategies to overcome resistance and improve outcomes in kidney cancer.
Purpose of the Study:
- To evaluate the efficacy of a novel therapeutic targeting exportin-1 (XPO1) in kidney cancer (RCC).
- To investigate the anti-cancer mechanisms of the XPO1 inhibitor KPT-330 in RCC.
- To assess the potential of KPT-330 as a treatment for both drug-naïve and drug-resistant RCC.
Main Methods:
- In vitro studies using RCC cell lines treated with KPT-330, including viability, apoptosis, and cell cycle assays.
- In vivo studies in RCC xenograft mouse models to evaluate KPT-330 efficacy and on-target effects.
- Establishment of KPT-330-resistant RCC cells to explore resistance mechanisms.
Main Results:
- KPT-330 demonstrated significant inhibition of RCC cell viability and induced apoptosis both in vitro and in vivo.
- Increased nuclear localization of p21, mediated by XPO1 inhibition, was identified as a key mechanism of KPT-330's action.
- KPT-330-resistant RCC cells remained sensitive to established RCC therapies like multi-kinase and mTOR inhibitors.
Conclusions:
- The orally available XPO1 inhibitor KPT-330 is a promising novel therapeutic target for kidney cancer.
- KPT-330 exhibits in vivo efficacy comparable to sunitinib, a current standard of care.
- Sequential or combination therapy with KPT-330 and existing RCC drugs offers a potential treatment strategy for both sensitive and resistant RCC patients.
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