Tyrosine Phosphorylation of Tubulin Isoform and Therapeutic Resistance in Prostate Cancer
Abstract
Androgen deprivation therapy (ADT) is the first-line treatment for patients with advanced prostate cancer (PCa). Although ADT is initially successful at reducing tumor burden and circulating PSA (prostate specific antigen) levels, majority of patients experience relapse into an incurable, androgen-insensitive disease known as castration-resistant prostate cancer (CRPC). Various treatments including taxanes (e.g., docetaxel and cabazitaxel), abiraterone, enzalutamide, and sipuleucel-T are currently approved for CRPC. Although current treatment options offer some survival benefit (3-6 months average), drug resistance is a common problem in advanced CRPC patients. Progression to CRPC and eventual failure of CRPC treatments remain the major cause of prostate cancer lethality. To improve the therapy for prostate cancer, it will be necessary to address the problems of progression to castration resistance and drug resistance. Therefore, understanding the biological mechanisms involved in castration resistance and drug resistance has emerged as a fundamental and urgent issue in prostate cancer research. In the area of cancer treatment, clinicians have to deal with two limitations: the difficulty to predict accurately the relapse after local treatment and the ability to anticipate ineffective adjuvant or systemic therapy. To date, the effectiveness of current targeted therapy for CRPC is limited by the lack of molecular markers to better define the subset of patients most likely to benefit from an adjuvant strategy after radical treatment and from chemotherapy at CRPC stage. Previous studies suggest that TUBB3 expression may be linked to multiple forms of resistance in PCa. Overexpression of TUBB3 in cancer cells can increase microtubule dynamics and confer docetaxel resistance in PCa. Our preliminary data showed that TUBB3 could be tyrosine phosphorylated by SRC kinase, whose activity is upregulated in CRPC. This study aims to elucidate a novel role of TUBB3 in epigenetic regulation for therapeutic resistance in PCa. If phosphorylation of TUBB3 induced by SRC kinase proves to be important for drug resistance in preclinical models and the level of TUBB3 tyrosine phosphorylation could predict response to docetaxel and/or dasatinib, the phospho-specific antibodies developed in this study and the gene signature associated with TUBB3 phosphorylation may potentially be used to stratify patients most likely to benefit from treatment of dasatinib and serve as a prognostic tool to predict resistance to hormonal therapy as well as chemotherapy in PCa. Furthermore, if nuclear-cytoplasmic shuttling of TUBB3 is important for modulating histone modifying enzyme EZH2 activity and drug response in preclinical PCa models, new combination therapy (e.g., docetaxel, dasatinib, and EZH2 inhibitor GSK126) could be developed to circumvent resistance in PCa.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510612
Entities
People
- Yun Qiu
Organizations
- United States Army
- University of Maryland, Baltimore