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. Drugs aimed at the DDR were limited by toxicity and need better molecular targets. We show that androgen deprivation of LNCaP increases expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that results in a cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of the TLK inhibitor, thioridazine (THD), impairs ATR and Chk1 activation, resulting in apoptosis. Treatment with THD suppressed the outgrowth of androgen-independent colonies of LNCaP. THD also inhibited growth of several PCa lines (including androgen independent). Administration of THD or bicalutamide was not effective in long-term inhibition of LNCaP xenografts, while combination remarkably inhibited tumor growth via bypass of the DDR. Xenografts of LNCaP cells overexpressing a NEK1-T141A mutant were durably suppressed with bicalutamide.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2019
- Accession Number
- AD1080155
Entities
People
- Arrigo De Benedetti
- Vibha Singh
Organizations
- Louisiana State University Shreveport