Targeting the TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of androgen independent prostate tumors

Standard therapy for advanced Prostate Cancer (PCa) consists of antiandrogens, which provide respite from disease progression, but ultimately fail resulting in the incurable phase of the disease: mCRPC. Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Combinat...

Full description

Saved in:
Bibliographic Details
Published in:International journal of cancer 2019-08, Vol.145 (4), p.1055-1067
Main Authors: Singh, Vibha, Jaiswal, Praveen Kumar, Ghosh, Ishita, Koul, Hari K., Yu, Xiuping, De Benedetti, Arrigo
Format: Article
Language:English
Subjects:
Androgen Antagonists - pharmacology
Androgens
Androgens - genetics
Animals
Antiandrogens
Apoptosis
Apoptosis - drug effects
Cancer
Cell cycle
Cell Cycle Checkpoints - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
CHK1 protein
Clinical trials
Deoxyribonucleic acid
DNA
DNA damage
DNA Damage - drug effects
Humans
Male
Medical research
Mice
Mice, Inbred NOD
Mice, SCID
Molecular Cancer Biology
Nek1 protein
NIMA-Related Kinase 1 - genetics
Prostate
Prostate cancer
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - genetics
Protein-Serine-Threonine Kinases - genetics
Receptors, Androgen - genetics
Thioridazine
Thioridazine - pharmacology
Toxicity
Tumors
Xenografts
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Standard therapy for advanced Prostate Cancer (PCa) consists of antiandrogens, which provide respite from disease progression, but ultimately fail resulting in the incurable phase of the disease: mCRPC. Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Combination therapy targeting the DNA Damage Response (DDR) has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. We now show that androgen deprivation therapy (ADT) of LNCaP cells results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that typically results in a temporary cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of the TLK specific inhibitor, thioridazine (THD), impairs ATR and Chk1 activation, establishing the existence of a ADT > TLK1 > NEK1 > ATR > Chk1, DDR pathway, while its abrogation leads to apoptosis. Treatment with THD suppressed the outgrowth of androgen‐independent (AI) colonies of LNCaP and TRAMP‐C2 cells cultured with bicalutamide. Moreover, THD significantly inhibited the growth of several PCa cells in vitro (including AI lines). Administration of THD or bicalutamide was not effective at inhibiting long‐term tumor growth of LNCaP xenografts. In contrast, combination therapy remarkably inhibited tumor growth via bypass of the DDR. Moreover, xenografts of LNCaP cells overexpressing a NEK1‐T141A mutant were durably suppressed with bicalutamide. Collectively, these results suggest that targeting the TLK1/NEK1 axis might be a novel therapy for PCa in combination with standard of care (ADT). What's new? Standard therapy for advanced Prostate Cancer (PCa) consists of anti‐androgens, which only provide temporary respite from disease progression to metastatic castrate‐resistant prostate cancer (mCRPC). Here, the authors show in the LNCaP cell model that the increased expression with ADT of TLK1B, a prosurvival checkpoint pathway that is enacted before conversion to androgen‐independent growth, offers a unique target for attacking more specifically PCa cells before their conversion to CRPC. Moreover, they suggest to re‐purpose thioridazine or other phenothiazine antipsychotic drugs as inhibitors of the TLK1 > Nek1 > ATR > Chk1 DNA Damage Response (DDR) axis for the early treatment of advanced PCa still responsive to ADT.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.32200