Examples of Resistance Developing Week 3 Draft 1
Patients exhibiting a resistance to existing therapies regarding BCR-ABL inhibition which leads to cancer programmed cell death and other long-term responses. A common observed mechanism of resistance is the acquisition of a second site mutation in the BCR-ABL itself. A mutation in the ATP binding pocket at the ‘gatekeeper’ residue theorine 315. This mutation results in the inhibition of optimal binding of inhibitors like imantinib, however, still permitting ATP hydrolysis, and this restores BCR-ABL signaling in the presence of inhibitors. Another example involves resistance to oncogene-targeted drugs which results as a mutation of alternate components of oncogene-induced signaling pathways. Mutant BRAF signal through the MAPK signaling pathways stimulates melanoma growth. One resistance mechanism to BRAF inhibitors is the acquisition of activation mutations in other MAPK pathways components like NRAS. These types of mutations restore MAPK oncogenic pathways signals despite continued therapeutic techniques of inhibitions of mutant BRAF. We know that activated RAS activates MAPKKK by binding to it and then this leads to the activation of MAPKK by phosphorylation, and then MAPK which then proceeds to activate proteins or transcription regulators in order to change protein activity or gene expression.
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