The rearranged during transfection(RET)is a receptor protein tyrosine kinase.Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer(NSCLC)and in thyroid cancer,but also increasingly in v...The rearranged during transfection(RET)is a receptor protein tyrosine kinase.Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer(NSCLC)and in thyroid cancer,but also increasingly in various types of cancers at low rates.In the last few years,two potent and selective RET protein tyrosine kinase inhibitors(TKIs),pralsetinib(BLU-667)and selpercatinib(LOXO-292,LY3527723)were developed and received regulatory approval.Although pralsetinib and selpercatinib gave high overall response rates(ORRs),<10%of patients achieved a complete response(CR).The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations,acquired alternative oncogenes,or MET amplification.RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib.Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials.However,it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs.Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.展开更多
基金Cancer research in Jie Wu’s laboratory was supported by NIH grants R01CA242845,R01CA273168,a PHF SEED grantOklahoma Center for the Advancement of Science and Technology(OCAST)grant HR19-026Additional support was provided by the Oklahoma Tobacco Settlement Endowment Trust,and the Peggy and Charles Stephenson Endowment,and NIH grants P30CA225520 and P20GM103639 to the institution.
文摘The rearranged during transfection(RET)is a receptor protein tyrosine kinase.Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer(NSCLC)and in thyroid cancer,but also increasingly in various types of cancers at low rates.In the last few years,two potent and selective RET protein tyrosine kinase inhibitors(TKIs),pralsetinib(BLU-667)and selpercatinib(LOXO-292,LY3527723)were developed and received regulatory approval.Although pralsetinib and selpercatinib gave high overall response rates(ORRs),<10%of patients achieved a complete response(CR).The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations,acquired alternative oncogenes,or MET amplification.RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib.Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials.However,it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs.Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.
