Dual inhibition of kif11 and the androgen receptor axis as a novel therapeutic approach for castration resistant prostate cancer

• Autores: Leticia Suarez Cabrera
• Directores de la Tesis: Anna Santamaría Margalef (dir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2022
• Idioma: inglés
• Tribunal Calificador de la Tesis: Ana Losada Valiente (presid.), Ibane Abasolo Olaortua (secret.), Violeta Serra Elizalde (voc.)
• Programa de doctorado: Programa de Doctorado en Bioquímica, Biología Molecular y Biomedicina por la Universidad Autónoma de Barcelona
• Materias:
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • Prostate cancer (PCa) is the second most common type of cancer and the fifth cause of cancer-related deaths among men, with almost 1.4 million of new cases and more than 375000 deaths worldwide in 2020. Most PCa related deaths occur after androgen-deprivation therapy (ADT) failure, when the tumor evolves to castration resistant prostate cancer (CRPC). Androgen receptor (AR) targeted therapies, such as enzalutamide, have shown to prolong CRPC patient survival, but most tumors become resistant through several mechanisms often related with the AR signaling pathway. Taxanes are a class of antimitotic agents that target microtubules and are the only chemotherapeutic drugs that have demonstrated clinical benefits after the development of AR-targeted therapy resistance. However, their related severe side effects and the development of resistance limit their clinical utility, leaving few therapeutic options to CRPC patients. Here we showed that overexpression of Kinesin Family Member 11 (KIF11), a motor protein essential for bipolar spindle formation and mitosis, is related with PCa progression, poor prognosis, the development of CRPC and hormonal therapy resistance. Inhibition of KIF11 with 4SC-205, a novel oral small-molecule inhibitor, effectively inhibits PCa growth in several preclinical models in vitro, ex vivo and in vivo. Moreover, based on the results of several gain and loss of function assays, we propose novel mechanistic insights based on a positive feed-back loop between the AR and KIF11 that could be contributing to PCa progression. Also, we demonstrated that the combination of KIF11 and AR inhibition by 4SC-205 and the AR inhibitor enzalutamide respectively, synergistically inhibits CRPC growth both, in vitro and in vivo. Altogether, our results indicate that KIF11 plays an important role in the development of CRPC and endocrine therapy resistance and we provide a good rationale for the development of a therapeutic strategy based on the combination of 4SC-205 and enzalutamide for the treatment of this lethal disease.