Overcoming mutation-based resistance to antiandrogens with rational drug design

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Enzalutamide is a second-generation antiandrogen for castration-resistant prostate cancer.
• Treatment response to enzalutamide is often limited due to resistance mechanisms.
• Androgen receptor (AR) mutations are a known cause of resistance to antiandrogen therapies.

Purpose of the Study:

• To prospectively identify novel AR mutations conferring resistance to enzalutamide.
• To understand the molecular mechanism of enzalutamide resistance.
• To discover new compounds that overcome enzalutamide resistance.

Main Methods:

• Reporter-based mutagenesis screen to identify AR mutations.
• Ectopic expression of mutated AR (F876L) to assess enzalutamide response.
• Molecular dynamics simulations to elucidate resistance mechanisms.
• Focused chemical screen to identify novel anti-androgen compounds.

Main Results:

• A novel AR mutation, F876L, was identified, converting enzalutamide into an AR agonist.
• AR F876L expression rescued enzalutamide-induced growth inhibition in prostate cancer cells.
• Molecular dynamics simulations revealed that F876L repositions helix 12, alleviating AR antagonism.
• Three novel compounds were identified that antagonize both wild-type AR and AR F876L, suppressing resistant prostate cancer cell growth.

Conclusions:

• The AR F876L mutation confers resistance to enzalutamide by altering AR conformation.
• Understanding resistance mechanisms can guide the development of next-generation therapies.
• Novel anti-androgen compounds targeting mutated AR offer a promising strategy for overcoming enzalutamide resistance in prostate cancer.