Efficacy comparison of fruquintinib,regorafenib monotherapy or plus programmed death-1 inhibitors for microsatellite stable metastatic colorectal cancer

BACKGROUND Regorafenib(R)and fruquintinib(F)are the standard third-line regimens for colorectal cancer(CRC)according to the National Comprehensive Cancer Network guidelines,but both have limited efficacy.Several phase 2 trials have indicated that R or F combined with immune checkpoint inhibitors can reverse immunosuppression and achieve promising efficacy for microsatellite stable or proficient mismatch repair(MSS/pMMR)CRC.Due to the lack of studies comparing the efficacy between F,R,F plus programmed death-1(PD-1)inhibitor,and R plus PD-1 inhibitors(RP),it is still unclear whether the combination therapy is more effective than monotherapy.AIM To provide critical evidence for selecting the appropriate drugs for MSS/pMMR metastatic CRC(mCRC)patients in clinical practice.METHODS A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital,and 313 MSS/pMMR mCRC patients were finally included.RESULTS A total of 313 eligible patients were divided into F(n=70),R(n=67),F plus PD-1 inhibitor(FP)(n=95)and RP(n=81)groups.The key clinical characteristics were well balanced among the groups.The median progression-free survival(PFS)of the F,R,FP,and RP groups was 3.5 months,3.6 months,4.9 months,and 3.0 months,respectively.The median overall survival(OS)was 14.6 months,15.7 months,16.7 months,and 14.1 months.The FP regimen had an improved disease control rate(DCR)(P=0.044)and 6-month PFS(P=0.014)and exhibited a better trend in PFS(P=0.057)compared with F,and it was also significantly better in PFS than RP(P=0.030).RP did not confer a significant survival benefit;instead,the R group had a trend toward greater benefit with OS(P=0.080)compared with RP.No significant differences were observed between the R and F groups in PFS or OS(P>0.05).CONCLUSION FP is superior to F in achieving 6-month PFS and DCR,while RP is not better than R.FP has an improved PFS and 6-month PFS compared with RP,but F and R had similar clinical efficacy.Therefore,FP may be a highly promising strategy in the treatment of MSS/pMMR mCRC.

Improved pinene production in a recombinant yeast by fusion linker optimization and chaperon coexpression

Pinene is an active natural monoterpene from plants and has important applications in favorings,fragrances,and pesticides.Especially,pinene dimers are regarded as renewable fuels with high density.However,the microbial pinene production was limited by the low activity pinene synthase.In this study,the pinene synthase activity was improved by fusion linker optimization and chaperon coexpression.To construct the pinene pathway in Saccharomyces cerevisiae,YPL062W gene was deleted to increase the MVA pathway precursor acetyl-CoA.Truncated 3-hydroxyl-3-methylglutaryl-CoA reductase(tHMG1),isopentenyl-diphosphate isomerase(IDI1),and farnesyl diphosphate synthase mutant(ERG20F96W−N127W)were then integrated to improve the GPP pool.Pinene synthase tPt1 was expressed in the constructed engineered yeast,and the titer of pinene reached 0.166 mg/L.GPP is the direct precursor of pinene,ERG20ww and tPt1 were fused by diferent linkers and orders to improve the accessibility of GPP.Pinene titer reached 9.94 mg/L by fusion these proteins in the order of ERG20ww and tPt1 and with a fexible linker(G)8.After that,several chaperons were coexpressed and the chaperon Sil1p improved the pinene titer to 10.2 mg/L with a yield of 1.63 mg/L·OD600.The results presented here provide novel information on the applications of protein fusion and protein chaperons in microbial pinene production.