Androgen deprivation is the standard systemic treatment for advanced prostate cancer

Androgen deprivation is the standard systemic treatment for advanced prostate cancer (PCa) but most patients ultimately develop castration-resistance. olaparib (OLA) to increase cytotoxicity to PCa cells. We further exhibited that targeting the c-Myb-TopBP1-ATR-Chk1 pathway by using the Chk1 inhibitor AZD7762 synergizes with OLA to increase PCa cytotoxicity. Our results reveal new mechanism-based therapeutic approaches for PCa by targeting PARP and the c-Myb-TopBP1-ATR-Chk1 pathway. INTRODUCTION Androgen deprivation is the standard systemic treatment for advanced prostate cancer (PCa) but most patients ultimately develop castration-resistance. The role of the androgen receptor (AR) in the development of castrate resistant prostate cancer (CRPC) is complex and despite decades of research remains poorly comprehended (1 2 Increased AR expression and stimulation of specific AR target genes have been shown to contribute through various mechanisms (3 4 Castration-resistance is also associated with de-repression of a specific set of AR target genes (3). A subset of aggressive tumors that display clinical features characteristic of small-cell prostate carcinoma show complete loss of AR expression (5). CRPC also exhibits resistance to other therapeutic brokers (6 7 Understanding the selection mechanisms and genetic pathways associated with drug resistance remains one of the most important problems in (+)-Bicuculline developing potentially curative therapies for advanced PCa. In an effort to identify molecular-pathologic events associated with the development of CPRC we initially performed candidate gene expression profiling of bone metastases derived from mCRPC patients and compared them to matched primary tumors or benign prostate tissue. Our analysis exhibited significantly higher c-Myb expression in bone metastases suggesting that c-Myb may play a role in the development of CRPC. is a transcription factor with diverse cellular functions including hematopoiesis cell proliferation differentiation survival and tumorigenesis (8). Gene fusion and copy-number alterations of suggest an oncogenic role in the (+)-Bicuculline progression of some breast prostate and head and neck cancers (9 10 c-Myb increased abundance of multiple genes involved in the progression of various malignant cells including proliferation (+)-Bicuculline genes and and and (8 11 While c-Myb expression has recently been associated with PCa cell proliferation survival and invasion in vitro (14) the regulation function and mechanistic associations of (+)-Bicuculline c-Myb in PCa remain largely unknown. Abundant DNA translocations and deletions arise in a highly interdependent manner in the PCa genome (15). For example a large percentage of PCa’s harbors fusions of TMPRSS2 to ERG or ETV1 which are considered drivers for advanced PCa (16). Maintenance of genomic integrity by DDR is critical to preventing tumorigenesis and DDR gene defects are common in multiple malignancies including PCa Rabbit polyclonal to TrkB. (17). Importantly the loss of components of one DNA repair pathway may be compensated for by the increased activity of other pathways which can provide necessary “stress support” for genetically unstable malignancy cells (18). However DDR gene defects or targeting specific DDR genes can present opportunities for cancer treatment. PARP1 is usually a key protein in the regulation of multiple forms of DNA repair processes (19 20 Numerous studies have exhibited “synthetic lethality” of PARP1 inhibitors with BRCA1/2 deficiency in cancer treatment (21 22 It was also reported that pharmacological inhibition of PARP1 inhibits ETS-positive but not ETS-negative prostate cancer xenograft growth (23). Chk1 has also been shown to be a central player in DDR network. Upon sensing DNA damage or replication stress the mutated- and Rad3-related (ATR) kinase is usually activated which in turn phosphorylates Chk1 leading to the activation of G2/M checkpoint and DNA repair (24 25 In this study we tested (i) whether c-Myb upregulation in advanced PCa is related to ADT or impairment of AR signaling; (ii) whether AR and c-Myb contribute to DDR and correlate with PCa progression; (iii) whether targeting PARP and c-Myb-regulated specific DDR signaling pathways can generate synergistic cytotoxicity to PCa. Our results reveal a new mechanism-based therapeutic strategy for PCa based on targeting PARP and the c-Myb-TopBP1-ATR-Chk1 signaling pathway. RESULTS c-Myb is usually transcriptionally activated by ADT or impairment of AR signaling Our immunohistochemical (IHC) analyses exhibited significantly higher.