Metastatic castration-resistant prostate cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by androgen receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, resulting in only a modest survival benefi t with antiandrogens. Therapeutic approaches that more effectively block the ARtranscriptional axis are urgently needed. Here, we investigated the molecular mechanism underlying the association between the transcriptional coactivator MED1 and AR as a vulnerability in AR-driven CRPC. MED1 undergoes CDK7-dependent phosphorylation at T1457 and physically engages AR at superenhancer sites, and is essential for AR-mediated transcription. In addition, a CDK7-specifi c inhibitor, THZ1, blunts AR-dependent neoplastic growth by blocking AR/MED1 corecruitment genome-wide, as well as reverses the hyperphosphorylated MED1-associated enzalutamide-resistant phenotype. In vivo , THZ1 induces tumor regression of AR-amplifi ed human CRPC in a xenograft mouse model. Together, we demonstrate that CDK7 inhibition selectively targets MED1-mediated, AR-dependent oncogenic transcriptional amplifi cation, thus representing a potential new approach for the treatment of CRPC. SIGNIFICANCE: Potent inhibition of AR signaling is critical to treat CRPC. This study uncovers a driver role for CDK7 in regulating AR-mediated transcription through phosphorylation of MED1, thus revealing a therapeutically targetable potential vulnerability in AR-addicted CRPC.

Despite the availability of PARP inhibitors for cancer therapy, a biomarker to clearly stratify patients for selection of this treatment remains lacking. Here we describe a radiotracer-based method that addresses this issue, using the novel compound [125I]KX1 as a PARP-1–selective radiotracer that can accurately measure PARP-1 expression in vitro and in vivo. The pharmacologic properties of the PARP radiotracer [125I]KX1 was characterized in multiple cell lines where single-agent sensitivity was correlated with [125I]KX1 binding to PARP-1. In vivo evaluation of [125I]KX1 verified in vitro results, validating PARP radiotracers to define PARP-1 enzyme expression as an in vivo biomarker. Notably, PARP-1 expression as quantified by [125I]KX1 correlated positively with the cytotoxic sensitivity of cell lines evaluated with PARP inhibitors. Overall, our results defined a novel technology with the potential to serve as a companion diagnostic to identify patients most likely to respond therapeutically to a PARP inhibitor.

Introduction: Poly (ADP-ribose) polymerase 1 (PARP-1) is the major target of clinical PARP inhibitors and is a potential predictive biomarker for response to therapy. Due to the limited success of PARP inhibitors as monotherapy, investigators have shifted the clinical role of PARP inhibitors to the adjuvant setting. In this study, we evaluate the radiotracer [18 F]FluorThanatrace ([ 18 F]FTT) as a marker of PARP expression in vitro and the associated biological implications of PARP-1 expression in PARP inhibitor treatment adjuvant to radiation therapy. Materials and Methods: SNU-251 (BRCA1-mutant) and SKOV3 (BRCA1-WT) cell lines were evaluated in vitro by using the radiotracer [18 F]FTT. Pharmacological binding assays were performed at baseline and were correlated with PARP-1 protein expression measured by Western blot protein analysis. Cell viability and clonogenic assays were used to characterize in vitro cytotoxicity for treatments, including: PARP inhibitors alone, radiation alone, and PARP inhibitor adjuvant to radiation. Western blot protein analysis was used to assess response to treatment by using cH2AX to measure DNA damage and PAR to measure the catalytic inhibition of PARP. Results: [

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