EGFR tyrosine kinase inhibitor HS-10182 increases radiation sensitivity in non-small cell lung cancers with EGFR T790M mutation

Objective:To investigate the potential of HS-10182,a second-generation epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI),as a radiosensitizer in non-small cell lung cancer(NSCLC).Methods:Two cell lines of NSCLCs,A549 that possesses wild-type(WT)EGFRs and H1975 that possesses EGFR L858R/T790M double mutations,were treated with HS-10182 at various concentrations,and cell viabilities were determined using the MTS assay.The cells were tested by clonogenic survival assays to identify the radiosensitivity of both groups.Western blot was performed to analyze the expression of phosphorylated EGFR,AKT,DNA-dependent protein kinase,and catalytic subunit(DNA-PKcs)proteins.Immunofluorescence analyses were performed to examine the formation and changes in nuclearγ-H2AX foci.Cell apoptosis was examined by flow cytometry and Western blots for cleaved caspase-3,-8,-9,and cleaved poly ADP-ribose polymerase(PARP).Furthermore,we established xenograft models in mice and the effects of different treatments on tumor growth were then assessed.Results:Clonogenic survival assays revealed that HS-10182 significantly enhanced the radiosensitivity of H1975 cells but not A549cells[dose enhancement ratios(DERs)=2.36(P<0.05)vs.1.43(P>0.05)].Western blot results showed that HS-10182 increased the levels of cleaved caspase-3,-8,-9,and cleaved PARP in H1975 cells but not in A549 cells.In addition,flow cytometry analysis showed that HS-10182 enhanced irradiation-induced apoptosis in H1975.Immunofluorescence results found that HS-10182increased the average number ofγ-H2AX foci after irradiation in H1975 cells,but not in A549 cells.Combined radiation and HS-10182 treatment increased the expression of DNA-PKcs but this increase was more significant in H1975 cells than in A549 cells.Moreover,HS-10182 suppressed the increased expression of Rad50 in H1975 cells in response to irradiation.In vivo experiments found that the combined therapy significantly inhibited tumor growth.Conclusions:HS-10182 enhances the radiosensitivity of H1975 cells which is possibly because that HS-10182 could enhance irradiation-induced apoptosis,increase irradiation-induced DNA damage,and cause a delay in DNA damage repair.Our findings suggest that radiotherapy combined HS-10182 is a novel treatment for lung cancer cells which have acquired the T790M mutation.HS-10182 could be brought to the clinic as a radiosensitizer in NSCLCs with the EGFR T790M mutation.

96-Week Treatment of Tenofovir Amibufenamide and Tenofovir Disoproxil Fumarate in Chronic Hepatitis B Patients

Background and Aims:Tenofovir amibufenamide(TMF)is a novel phosphoramidated prodrug of tenofovir with nonin-ferior efficacy and better bone and renal safety to tenofovir disoproxil fumarate(TDF)in 48 weeks of treatment.Here,we update 96-week comparison results.Methods:Patients with chronic hepatitis B were assigned(2:1)to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks.The virological suppression was defined as HBV DNA levels<20 IU/mL at week 96.Safety was evaluated thoroughly with focusing on bone,renal,and metabolic pa-rameters.Results:Virological suppression rates at week 96 were similar between TMF and TDF group in both HBeAg-positive and HBeAg-negative populations.Noninferior efficacy was maintained in the pooled population,while it was first achieved in patients with HBV DNA≥7 or 8 log10 IU/mL at baseline.Non-indexed estimated glomerular filtration rate for renal safety assessment was adopted,while a smaller decline of which was seen in the TMF group than in the TDF group(p=0.01).For bone mineral density,patients receiv-ing TMF displayed significantly lower reduction levels in the densities of spine,hip,and femur neck at week 96 than those receiving TDF.In addition,the lipid parameters were stable after week 48 in all groups while weight change still showed the opposite trend.Conclusions:TMF maintained similar efficacy at week 96 compared with TDF with continued superior bone and renal safety profiles(NCT03903796).