Targeting the TLK1/NEK1 Axis in PCa
Abstract
The mainstay therapy for prostate cancer (PCa) progressed beyond localized treatments is androgen-deprivation therapy (ADT), which is initially effective in providing remission of the disease in most patients. However, after a mean time of 2-3 years, frequently the disease progresses despite hormonal manipulation (termed castrate-resistant PCa or CRPC). Treatments directed at preventing or delaying progression to CRPC have the best chance of having immediate impact on the disease. For this, it is critical to understand the changes that occur in PCa cells during the period of adaptation to ADT. Two pathways are currently known to be activated in androgen-sensitive PCa cells following depletion of androgen: (1) a DNA damage response (DDR) that functions to arrest DNA replication in the unfavorable growth condition and activate DNA repair pathways and (2) the survival PI3K/AKT/mTOR/eIF4E pathway. During our studies we have identified a key target in the protein kinase TLK1B that converges on both pathways. The mechanism of action of TLK1B and its target proteins, however, is only now beginning to be elucidated, and our proposed work will provide a key contribution to advancing the field of PCa research and the DDR in general. Specifically, we want elucidate the contribution of NEK1, which we discovered as a key target of TLK1B, in mediating key aspects of the DDR. We further hypothesize that inhibition of the TLK1N/NEK1 axis will result in bypass of the DDR in response to ADT, and hence result in excess DNA replication induced damage that will lead to death of PCa cells before they can convert to androgen insensitive. We have identified specific inhibitors of TLK1B and found several in the class of phenothiazine (PTH) antipsychotics, which we propose to repurpose for the treatment of PCa to improve response to ADT. Since these are well-tested drugs, if our work is successful, it may not take long to achieve a patient-related outcome with a clinical trial. PTHs have been used for over 30 years for severe psychotic illnesses for prolonged periods with relatively low side effects. These include a small increased risk of cardiac arrhythmia and extrapyramidal toxicity with long-term use. We believe that the relatively small increased risk for side effects from the use of PTH inhibitors of the TLK1/NEK1 axis can be outweighed by a more complete response to ADT, perhaps preventing progression to CRPC altogether. There are competitive advantages that can derive from our proposed modified treatment for advanced PCa prior to progression to CRPC (target patients). The DDR includes the activation of numerous cellular activities that prevent duplication of DNA lesions and maintain genomic integrity, which is critical for the survival of normal and cancer cells. Specific genes involved in the DDR such as BRCA1/2 and P53 are often mutated during PCa progression, increasing the genomic instability of cancer cells. These events may render PCa cells particularly sensitive to inhibition of specific DDR pathways, such as PARP in homologous recombination DNA repair and Chk1 (a target of NEK1) in cell cycle checkpoint and DNA repair, creating opportunities for synergistic cytotoxicity. Recent reports highlight the critical role of androgen receptor (AR) as a regulator of DDR genes, providing a rationale for combining DNA damaging agents or targeted DDR inhibitors with AR inhibition as treatment for aggressive disease. Despite this promise, PARP inhibitors have not been effective for PCa and showed some effect only in tumors with HR deficiency (BRCA1/2). Targeting the DNA DSB repair machinery (ATM and DNA-PK) has been successful in sensitizing PCa cells to radiation and doxorubicin, as we have found by targeting TLK1 (published in 2013). What is unique about our preliminary findings in this proposal is that the TLK1/NEK1 axis also appears to be critical for the initial survival of androgen-sensitive PCa cells following ADT. Ther
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710417
Entities
People
- Arrigo De Benedetti
Organizations
- Louisiana State University Health Sciences Center Shreveport
- United States Army