Lecture 8 Flashcards
CML (Chronic Myelogenous Leukemia)
Characteristics: increased number of granulocytes and their precursors in the peripheral blood
Philadelphia Chromosome
Comes from a chromosomal translocation between chromosomes 9 & 22 (responsible for CML)
Bcr-Abl
Oncogene produced by the chromosomal translocation in CML
- non receptor tyrosine kinase
Gleevec pt. I
Primary drug used for targeted therapy of CML
Tyrosine kinase inhibitor
Gleevec pt. II
Success: almost all CML patients have a complete response to Gleevec
For most patients responses last for years but drug resistance develops in ~10-15% of patients
Gleevec Resistance
Bcr-Abl gene amplification & mutation of Bcr-Abl decreases Gleevec binding affinity
Treated using Dasatinib
Metastatic Melanoma
Generated by mutated melanocytes
B-raf (V600E)
Primary driver oncogene for metastatic melanomas
Serine/threonine kinase
PLX 4032 (Zelboraf)
Treated metastatic melanomas and targeted B-raf (V600E)
Also inhibits regular B-raf but at a 10-fold higher drug concentration
PLX 4032 pt. II
High % of patients achieved large success responses, but resistance developed
Resistance to PLX 4032
Up-regulation of PDGF receptors which activated a new survival pathway
Also mutation of N-ras which stimulated c-RAF to reactivate MAPK survival pathways