Phenethyl Isothiocyanate Enhances the Cytotoxic Effects of PARP Inhibitors in High-Grade Serous Ovarian Cancer Cells.

While PARP inhibitor (PARPi) therapies have shown promising results in the treatment of high-grade serous ovarian cancer (HGSOC) harboring homologous recombination deficiencies, primary resistance to PARPi frequently occurs and even initial responders may eventually become resistant. Therefore, the development of novel effective combinatorial strategies to treat HGSOC is urgently needed. Here, we report that H2O2-induced oxidative stress sensitized HGSOC cells to PARPi BMN 673. Furthermore, Phenethyl isothiocyanate (PEITC) as a ROS-inducing agent significantly enhanced the cytotoxic effects of BMN 673. Mechanistically, combined use of PEITC and BMN 673 resulted in ROS overproduction and accumulation, enhanced DNA damage, G2/M arrest and apoptosis, all of which were significantly reversed by the ROS scavenger N-Acetyl-L-cysteine. We also showed that while PEITC did not further enhance the ability of BMN 673 on PARP1 trapping in HGSOC cells, the therapeutic effects of the PEITC/BMN 673 combination were at least in part dependent on the presence of PARP1. Importantly, the PEITC/BMN 673 combination potently abrogated the growth of HGSOC tumor spheroids and patient-derived organoid models of HGSOC and cervical cancer. Our findings provide a basis for further investigation of the utility of PARPi combination regimen in HGSOC and cervical cancer through ROS-mediated mechanisms.

BTF3 confers oncogenic activity in prostate cancer through transcriptional upregulation of Replication Factor C.

High levels of Basic Transcription Factor 3 (BTF3) have been associated with prostate cancer. However, the mechanisms underlying the role of BTF3 as an oncogenic transcription factor in prostate tumorigenesis have not been explored. Herein, we report that BTF3 confers oncogenic activity in prostate cancer cells. Mechanistically, while both BTF3 splicing isoforms (BTF3a and BTF3b) promote cell growth, BTF3b, but not BTF3a, regulates the transcriptional expression of the genes encoding the subunits of Replication Factor C (RFC) family that is involved in DNA replication and damage repair processes. BTF3 knockdown results in decreased expression of RFC genes, and consequently attenuated DNA replication, deficient DNA damage repair, and increased G2/M arrest. Furthermore, knockdown of the RFC3 subunit diminishes the growth advantage and DNA damage repair capability conferred by ectopic overexpression of BTF3b. Importantly, we show that enforced BTF3 overexpression in prostate cancer cells induces substantial accumulation of cisplatin-DNA adducts and render the cells more sensitive to cisplatin treatment both in vitro and in vivo. These findings provide novel insights into the role of BTF3 as an oncogenic transcription factor in prostate cancer and suggest that BTF3 expression levels may serve as a potential biomarker to predict cisplatin treatment response.

MYC status as a determinant of synergistic response to Olaparib and Palbociclib in ovarian cancer.

BACKGROUND: While PARP inhibitors and CDK4/6 inhibitors, the two classes of FDA-approved agents, have shown promising clinical benefits, there is an urgent need to develop new therapeutic strategies to improve clinical response. Meanwhile, extending the utility of these inhibitors beyond their respective molecularly defined cancer types is challenging and will likely require biomarkers predictive of treatment response especially when used in a combination drug development setting. METHODS: The effects of PARP inhibitor Olaparib and CDK4/6 inhibitor Palbociclib on ovarian cancer cells lines including those of high-grade serous histology were examined in vitro and in vivo. We investigated the molecular mechanism underlying the synergistic effects of drug combination. FINDINGS: We show for the first time that combining PARP and CDK4/6 inhibition has synergistic effects against MYC overexpressing ovarian cancer cells both in vitro and in vivo. Mechanistically, we find that Palbociclib induces homologous recombination (HR) deficiency through downregulation of MYC-regulated HR pathway genes, causing synthetic lethality with Olaparib. We further demonstrate that MYC expression determines sensitivity to combinatorial treatment with Olaparib and Palbociclib. INTERPRETATION: Our data provide a rationale for clinical evaluation of therapeutic synergy of these two classes of inhibitors in ovarian cancer patients whose tumors show high MYC expression and who do not respond to PARP inhibitors or CDK4/6 inhibitors monotherapies. FUND: This work was supported by the National Natural Science Foundation of China [81672575, 81874111, 81472447 to HC; 81572586 and 81372853 to PL], and the Liaoning Provincial Key Basic Research Program for Universities [LZ2017002 to HC].