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Tyrosine Kinase Inhibitors (Imatnib (Bcr/Abl from Philadelphia chromosome:…
Tyrosine Kinase Inhibitors
Imatnib
Bcr/Abl from Philadelphia chromosome: chromosomal translocation activate proto-oncogene (22/9). Bcr controls Abl protein kinase expression
Inhibits PDGF (receptor tyrosine kinase)
Inhibits Bcr/Abl (oncogenic cytoplasmic kinase) -> unique for CML
Greatly improved CML prognosis
MoA: binds to Bcr/Abl enzyme and prevents ATP binding (and therefore prevents phosphorylation of target protein)
CML
clonal expansion of pleuripotent hematopoetic stem cells
myeloproliferative disorder
Imatnib resistance
15%: Bcr/Abl amplification
Also drug efflux, extracellular sequestration of drug, secondary kinase activation
75%: Bcr/Abl kinase domain mutation
Palbocyclib
2016/17: in combination with aromatase inhibitor (1st line)
CDK4/6 inhibitor: stops phosphorylation of Rb -> E2F is not freed from Rb and cell cannot pass restriction point
2015/16 - in combination with ER antagonist (if disease progresses with endocrine therapy)
Tamoxifen stops ER producing Cyclin D
tx ER+, HER2- (luminal A) locally advanced & metastatic
breast cancer in post-menopausal women