Targeting the TLK1/NEK1 Axis in PCa
Abstract
Standard therapy for advanced Prostate Cancer (PCa) consists of anti-androgens, which provide respite from disease progression, but ultimately fail resulting in incurable mCRPC. We recently uncovered the critical TLK1 greater than NEK1 greater than ATR greater than Chk1 axis in mediating the DDR and cell cycle checkpoint while transiting from Androgen Sensitive to Insensitive growth for LNCaP and TRAMP-C2 cells. However, we did not know the generality of this pathway in PCa progression since there are few cell lines where the transition has been studied. Furthermore, the identification of Nek1, and more importantly the TLK-mediated phosphorylation of T141, has never been studied in PCa biopsies. We reported the first study of a PCa TMA of p-Nek1-T141 and correlation to the Gleason score. In addition, we found that TRAMP mice treated with a novel TLK 1inhbitor we generated (J54), following castration did not recover cancerous growth of their prostates. Moreover, we recapitulated the process of translational increase in TLK1B expression in a nave PDX model that was established from an AR adenocarcinoma. Therefore, we believe that this TLK1-Nek1 mediated DDR axis is likely to be a common adaptive response during the transition of PCa cells toward androgen-insensitive growth, and hence CRPC. Progression, which has the potential to be targeted with THD and other TLK or Nek1 inhibitors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2021
- Accession Number
- AD1149326
Entities
People
- Arrigo De Benedetti
Organizations
- Louisiana State University