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Drug-Induced-Liver-Injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market, and this is partially due to the inability to identify patients who are at risk 1 . Here, we developed a polygenic risk score (PRS) for DILI by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies (GWAS) 2 . The PRS predicted the susceptibility to DILI in patients treated with fasiglifam, amoxicillin-clavulanate or flucloxacillin, and in primary hepatocytes and stem cell-derived organoids from multiple

ts ET24 cells are a novel temperature-sensitive (ts) mutant for cell proliferation of hamster BHK21 cells. The human genomic DNA which rescued the temperature-sensitive lethality of ts ET24 cells was isolated and screened for an open reading frame in the deposited human genomic library. X chromosomal DBX gene encoding the RNA helicase, DEAD-BOX X isoform, which is homologous to yeast Ded1p, was found to be defective in this mutant. The single point mutation (P267S) was localized between the Motifs I and Ia of the hamster DBX of ts ET24 cells. At the nonpermissive temperature of 39.5 degrees C, ts ET24 cells were arrested in the G1-phase and survived for more than 3 days. In ts ET24 cells, total protein synthesis was not reduced at 39.5 degrees C for 24 h, while mRNA accumulated in the nucleus after incubation at 39.5 degrees C for 17 h. The amount of cyclin A mRNA decreased in ts ET24 cells within 4 h after the temperature shift to 39.5 degrees C, consistent with the fact that the entry into the S-phase was delayed by the temperature shift.

Erlotinib (ERL), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, shows notable efficacy against non-small cell lung cancer (NSCLC) harboring EGFR mutations. Bevacizumab (BEV), a humanized monoclonal antibody to vascular endothelial cell growth factor (VEGF), in combination with ERL (BEV1ERL) significantly extended progression-free survival in patients with EGFR-mutated NSCLC compared with ERL alone. However, the efficacy of BEV1ERL against EGFR-mutated NSCLC harboring T790M mutation or MET amplification, is unclear. Here, we examined the antitumor activity of BEV1ERL in four xenograft models of EGFR-mutated NSCLC (three harboring ERL resistance mutations). In the HCC827 models (exon 19 deletion: DEL), ERL significantly inhibited tumor growth by blocking EGFR signal transduction. Although there was no difference between ERL and BEV1ERL in maximum tumor growth inhibition, BEV1ERL significantly suppressed tumor regrowth during a drugcessation period. In the HCC827-EPR model (DEL1T790M) and HCC827-vTR model (DEL1MET amplification), ERL reduced EGFR signal transduction and showed less pronounced but still significant tumor growth inhibition than in the HCC827 model. In these models, tumor growth inhibition was significantly stronger with BEV1ERL than with each single agent. In the NCI-H1975 model (L858R1T790M), ERL did not inhibit growth or EGFR signal transduction, and BEV1ERL did not inhibit growth more than BEV. BEV alone significantly decreased microvessel density in each tumor. In conclusion, addition of BEV to ERL did not enhance antitumor activity in primarily ERL-resistant tumors with T790M mutation; however, BEV1ERL enhanced antitumor activity in T790M mutation-or MET amplification-positive tumors as long as their growth remained significantly suppressed by ERL.Patients with non-small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFR) gene, such as an E746-A750 deletion in exon 19 (DEL) and L858R mutation in exon 21, showed significant improvement in progression-free survival (PFS) when treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib (ERL), as compared with chemotherapies.

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