Steelman, L.S., et. al. give a comprehensive introduction to the roles of the Ras pathway in leukemia therapy. The paper is attached as a PDF.
I will try to recap their article in my own words below.
The Ras pathway, also known as the Ras/Raf/mitogen-activiated proten kinase (MEK) or extracellular signal-regulated kinase (ERK) signaling pathway, plays a key role in leukemia therapy. The pathway regulates the transmission of signals from membrane-bound receptors to the cell's control center (nucleus) and specifically transmits signals that lead to cell proliferation. Once activated, the Ras/Raf/MEK/ERK pathway can then activate cell survival pathways, alter the cell cycle, as well as regulate apoptosis.
Like many signaling pathways, the Ras pathway involves a phosphorylation cascade, kinases, and multiple supporting proteins (exchange, adaptor, and scaffolding).
The Ras pathway is activated by growth factors, and particularly, can be activated by receptor tyrosine kinases (sound familiar? hmm... NTRK: neurotrophic tyrosine kinase receptor...). A bunch of proteins continuously get activated/phosphorylated upon the signal of another and the cascade continues.
Location is important. Where the mutation occurs, where the signaling molecules are--these details affect the outcome of certain inhibitors.
There are two types of mutations: Class I and Class II. Class I mutations cause cell proliferation while class II mutations are based on the chromosome and transcription factors. Example of known gene mutation: FLT3, which occurs in 20-25% of AML (acute myeloid leukemia) patients
Based on the article, chemotherapeutic drugs may have the ability to activate the Ras pathway (which we don't necessarily, want--it may amplify later drug resistance and contribute to harmful effects to DNA repair mechanisms) and actually keep the pathway activated for a prolonged period of time, thereby stimulating cell survival. *Big question: How do we find a way to control the expression/activation of this pathway in order to improve leukemia therapy (instead of its current reverse effects)?
RKIP, a scaffolding protein, has been found to inhibit the activity of MEK and ERK transciption factors.
Still, there are problems:
Some mutations hinder the sensitivity of Ras inhibitors, and others just cause overexpression of growth factors.
Even though mutations create abnormalities in Ras pathway expression, the biggest problem is the eventual drug resistance from the leukemic cells, as stated by this article. This is an important obstacle to tackle, especially with the objective of developing an effective cancer drug/personalized medicine for the future.