Which signaling pathway and protein to selea to mitigate the patient's expected drug resistance?The number of possibilities facing the physician is massive,and the drug combination should fit the patient status.He...Which signaling pathway and protein to selea to mitigate the patient's expected drug resistance?The number of possibilities facing the physician is massive,and the drug combination should fit the patient status.Here,we briefly review current approaches and data and map an innovative patient-specific strategy to forecast drug resistance targets that centers on parallel(or redundant)proliferation pathways in specialized cells.It considers the availability of each protein in each pathway in the specific cell,its activating mutations,and the chromatin accessibility of its encoding gene.The construction of the resulting Proliferation Pathway Network Atlas will harness the emerging exascale computing and advanced artificial intelligence(Al)methods for therapeutic development.Merging the resulting set of targets,pathways,and proteins,with current strategies will augment the choice for the attending physicians to thwart resistance.展开更多
Dear Editor,B-Raf,the main effector of Ras in the mitogen-activated protein kinase(MAPK)pathway,is among the most highly mutated kinases in human cancer[1].About 40%-60%of melanoma patients harbor B-Raf mutations,of w...Dear Editor,B-Raf,the main effector of Ras in the mitogen-activated protein kinase(MAPK)pathway,is among the most highly mutated kinases in human cancer[1].About 40%-60%of melanoma patients harbor B-Raf mutations,of which∼90%involve V600E and V600K.B-RafV600E is more frequent(60%-80%)than B-RafV600K(10%-30%).Substitution of a Val codon by Glu requires a single nucleotide change,whereas Val to Lys requires two[2].This is in line with melanoma patients harboring the V600K mutation,who usually suffer from higher sun exposure that may induce increased DNA damage[3].Since both mutations occur at the same position of the kinase domain and are mutated to charged residues,it was believed that the B-Raf V600E and V600K mutantswould share a similar behavior,and in clinical trials,patients with V600E and V600K mutations have been recruited into the same cohort.展开更多
基金This project has been funded in whole or in part with federal funds from the National Cancer Institute,National Institutes of Health,under contract HHSN261200800001EThis research was supported[in part]by the Intramural Research Program of NIH,National Cancer Institute,Center for Cancer Research.
文摘Which signaling pathway and protein to selea to mitigate the patient's expected drug resistance?The number of possibilities facing the physician is massive,and the drug combination should fit the patient status.Here,we briefly review current approaches and data and map an innovative patient-specific strategy to forecast drug resistance targets that centers on parallel(or redundant)proliferation pathways in specialized cells.It considers the availability of each protein in each pathway in the specific cell,its activating mutations,and the chromatin accessibility of its encoding gene.The construction of the resulting Proliferation Pathway Network Atlas will harness the emerging exascale computing and advanced artificial intelligence(Al)methods for therapeutic development.Merging the resulting set of targets,pathways,and proteins,with current strategies will augment the choice for the attending physicians to thwart resistance.
基金the National Cancer Institute,National Institutes of Health,under contract HHSN261201500003I.
文摘Dear Editor,B-Raf,the main effector of Ras in the mitogen-activated protein kinase(MAPK)pathway,is among the most highly mutated kinases in human cancer[1].About 40%-60%of melanoma patients harbor B-Raf mutations,of which∼90%involve V600E and V600K.B-RafV600E is more frequent(60%-80%)than B-RafV600K(10%-30%).Substitution of a Val codon by Glu requires a single nucleotide change,whereas Val to Lys requires two[2].This is in line with melanoma patients harboring the V600K mutation,who usually suffer from higher sun exposure that may induce increased DNA damage[3].Since both mutations occur at the same position of the kinase domain and are mutated to charged residues,it was believed that the B-Raf V600E and V600K mutantswould share a similar behavior,and in clinical trials,patients with V600E and V600K mutations have been recruited into the same cohort.
