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Published on: December 9, 2016
Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to
Geun Taek Lee1, Naoya Nagaya1, Jenny Desantis2
1Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, and Division of Urology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
Abstract:
Although second-line antiandrogen therapy (SAT) is the standard of care in men with castration-resistant prostate cancer (CRPC), resistance inevitably occurs. One major proposed mechanism of resistance to SAT involves the emergence of androgen receptor (AR) splice variant-7, AR-V7. Recently, we developed MTX-23 using the principle of proteolysis targeting chimera (PROTAC) to target both AR-V7 and AR-full length (AR-FL). MTX-23 has been designed to simultaneously bind AR's DNA binding domain (DBD) and the Von Hippel-Lindau (VHL) E3 ubiquitin ligase. Immunoblots demonstrated that MTX-23's degradation concentration 50% (DC50) for AR-V7 and AR-FL was 0.37 and 2 μmol/L, respectively. Further studies revealed that MTX-23 inhibited prostate cancer cellular proliferation and increased apoptosis only in androgen-responsive prostate cancer cells. The antiproliferative effect of MTX-23 was partially reversed when either AR-V7 or AR-FL was overexpressed and was completely abrogated when both were overexpressed. To assess the potential therapeutic value of MTX-23, we next generated 12 human prostate cancer cell lines that are resistant to the four FDA-approved SAT agents-abiraterone, enzalutamide, apalutamide, and darolutamide. When resistant cells were treated with MTX-23, decreased cellular proliferation and reduced tumor growth were observed both in vitro and in mice. These results collectively suggest that MTX-23 is a novel PROTAC small molecule that may be effective against SAT-resistant CRPC by degrading both AR-V7 and AR-FL.
Insights
A new PROTAC molecule, MTX-23, effectively degrades both full-length androgen receptor (AR-FL) and AR-V7, offering a potential treatment for castration-resistant prostate cancer (CRPC) that is resistant to standard antiandrogen therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Second-line antiandrogen therapy (SAT) is standard for castration-resistant prostate cancer (CRPC).
- Resistance to SAT often involves the androgen receptor (AR) splice variant-7 (AR-V7).
- Existing therapies face challenges due to resistance mechanisms like AR variants.
Purpose of the Study:
- To develop a novel therapeutic agent targeting both AR-full length (AR-FL) and AR-V7.
- To evaluate the efficacy of the PROTAC molecule MTX-23 in preclinical models of prostate cancer.
Main Methods:
- Developed MTX-23, a proteolysis targeting chimera (PROTAC) designed to bind AR's DNA binding domain and VHL E3 ligase.
- Assessed MTX-23's degradation efficacy (DC50) against AR-V7 and AR-FL using immunoblots.
- Investigated MTX-23's effects on prostate cancer cell proliferation and apoptosis in vitro.
- Generated and treated SAT-resistant prostate cancer cell lines with MTX-23.
- Evaluated MTX-23's efficacy in reducing tumor growth in mouse models.
Main Results:
- MTX-23 demonstrated degradation concentration 50% (DC50) values of 0.37 μmol/L for AR-V7 and 2 μmol/L for AR-FL.
- MTX-23 inhibited proliferation and increased apoptosis in androgen-responsive prostate cancer cells.
- Overexpression of AR-V7 or AR-FL partially reversed MTX-23's antiproliferative effect; co-overexpression abrogated it.
- MTX-23 reduced proliferation and tumor growth in SAT-resistant prostate cancer cell lines in vitro and in vivo.
Conclusions:
- MTX-23 is a novel PROTAC molecule capable of degrading both AR-V7 and AR-FL.
- MTX-23 shows therapeutic potential against SAT-resistant CRPC.
- Targeting both AR variants simultaneously represents a promising strategy for overcoming treatment resistance.
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