Many cancers lack functional expression of the enzyme argininosuccinate synthetase 1(ASS1)that is necessary for synthesis of L-arginine.These cancers must import arginine for survival and growth,and this reliance can ...Many cancers lack functional expression of the enzyme argininosuccinate synthetase 1(ASS1)that is necessary for synthesis of L-arginine.These cancers must import arginine for survival and growth,and this reliance can be targeted by arginine-degrading extracellular enzymatic drugs,most commonly PEGylated arginine deiminase.These enzymes can become targets of the immune system,reducing their effectiveness,but PEGylation improves the in vivo stability.Arginine deprivation causes cell death in some cancers,but others gain resistance by expressing ASS1 after a starvation response is induced.Other resistance mechanisms are possible and explored,but these have not been observed specifically in response to arginine deprivation.Future studies,especially focusing on the mechanisms of ASS1 upregulation and metabolic adaptations,may yield insights into preventing or taking advantage of resistance adaptations to make arginine deprivation therapy more effective.展开更多
基金BAVT-reports a one year grant from Polaris,Inc.in 2014,unrelatedBasic Science Grant Funding from Pfizer,Tracon,and Merck+3 种基金consulting fees from Epizyme,Lilly,CytRX,Janssen,Immune Design,Daiichi Sankyo,Bayer,Plexxicon and Adaptimmunespeaking fees from Caris,Janseen and LillyTravel support from Lillyand is the overall principle investigator on(NCT03449901).
文摘Many cancers lack functional expression of the enzyme argininosuccinate synthetase 1(ASS1)that is necessary for synthesis of L-arginine.These cancers must import arginine for survival and growth,and this reliance can be targeted by arginine-degrading extracellular enzymatic drugs,most commonly PEGylated arginine deiminase.These enzymes can become targets of the immune system,reducing their effectiveness,but PEGylation improves the in vivo stability.Arginine deprivation causes cell death in some cancers,but others gain resistance by expressing ASS1 after a starvation response is induced.Other resistance mechanisms are possible and explored,but these have not been observed specifically in response to arginine deprivation.Future studies,especially focusing on the mechanisms of ASS1 upregulation and metabolic adaptations,may yield insights into preventing or taking advantage of resistance adaptations to make arginine deprivation therapy more effective.
