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DNA replication, recombination, and repair are highly interconnected processes the disruption of which must be coordinated in cancer. HERC2, a large HECT protein required for homologous recombination repair, is an E3 ubiquitin ligase that targets breast cancer suppressor BRCA1 for degradation. Here, we show that HERC2 is a component of the DNA replication fork complex that plays a critical role in DNA elongation and origin firing. In the presence of BRCA1, endogenous HERC2 interacts with Claspin, a protein essential for G 2 -M checkpoint activation and replication fork stability. Claspin depletion slowed S-phase progression and additional HERC2 depletion reduced the effect of Claspin depletion. In addition, HERC2 interacts with replication fork complex proteins. Depletion of HERC2 alleviated the slow replication fork progression in Claspin-deficient cells, suppressed enhanced origin firing, and led to a decrease in MCM2 phosphorylation. In a HERC2-dependent manner, treatment of cells with replication inhibitor aphidicolin enhanced MCM2 phosphorylation. Taken together, our results suggest that HERC2 regulates DNA replication progression and origin firing by facilitating MCM2 phosphorylation. These findings establish HERC2 as a critical function in DNA repair, checkpoint activation, and DNA replication. Cancer Res; 71(17); 5621-5. Ó2011 AACR.

We conducted a phase I/II study to investigate the safety and efficacy of nivolumab (NIVO) with paclitaxel (PTX) plus ramucirumab (RAM). Experimental Design: Patients with advanced gastric cancer (AGC) refractory to first-line chemotherapy were included. Patients received NIVO (3 mg/kg on days 1 and 15) combined with PTX (80 mg/m2 on days 1, 8, and 15) and RAM (8 mg/kg on days 1 and 15) every 4 weeks. After feasibility evaluation in 6 patients (phase I), 37 additional patients were enrolled to the phase II with the primary endpoint of 6-month progression-free survival (PFS) rate with two-sided 80% CI. The combined positive score (CPS) was defined as the number of programmed death-ligand 1-positive cells divided by the total number of viable tumor cells, multiplied by 100. Results: Forty-three patients were enrolled. Of these, 60.5% had CPS≥1. Dose-limiting toxicities were observed in 2 patients, and the recommended dose was determined as level 1. Thirty-nine (90.7%) patients experienced treatment-related adverse events ≥ grade 3 and 14 (32.6%) patients experienced immune-related adverse events ≥ grade 3. The overall response rate was 37.2% (95%CI, 23.0%-53.5%) and the 6-month PFS rate was 46.5% (80% CI, 36.4%-55.8%) (P=0.067). Median survival time was 13.1 months Research.

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