Determinants of Response to Microtubule Stabilizing Drugs
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: The taxane compounds, paclitaxel (Taxol) and docetaxel (Taxotere), have been important components of chemotherapy regimens to treat breast cancer. However, a patient’s intrinsic or acquired resistance to these drugs has largely deterred their widespread clinical utility. They are mainly used to treat metastatic disease and in situations where other therapies, such as SERMs, have failed the patient. Taxanes specifically target the cellular microtubules and ultimately cause cell death, since microtubules are essential for cell division. The best studied mechanism of resistance to taxanes is the upregulation of a protein called P-glycoprotein (P-gp) which pumps these drugs out of cells; however, there is evidence that the majority of taxane resistant breast tumors do not function via the P-gp mechanism. Thus, elucidating these additional taxane resistance mechanisms remains an important question in breast cancer biology. 
 
 
 
 
 
 
 
 The central hypothesis of this application is that altered levels and/or aberrant modification of microtubule associated proteins, MAP-Tau, MAP4 and MAP2, confer resistance to taxanes as a result of altering the properties of the drugs' ability to successfully target microtubules. To test this hypothesis, our laboratory has developed several taxane resistant variants from four breast cancer cell lines which do not exhibit the P-gp mechanism of resistance and which, therefore, became resistant to taxanes via unknown alternative mechanisms. These cell lines will serve as preclinical models that will help us evaluate the expression levels and modifications of MAP-Tau, MAP4 and MAP2 proteins. We also have a commercially available breast cancer cell line which will allow us to increase the levels of these microtubule proteins in a controlled manner and determine whether the higher levels will lead to resistance to taxanes. Conversely, we can decrease the levels of these proteins using a special technology, called RNA silencing (RNAi), and examine whether the decreased levels will have an effect on resistance to taxanes. Finally, we will examine whether modification of these proteins via attaching a chemical group, called phosphate, to specific amino acid residues plays a role in modulating response to taxanes. We plan to mutate these residues so that the chemical modification can either no longer occur or persists permanently. This approach will allow us to determine whether the cells show differential survival after treatment with taxanes.
 
 
 
 
 
 
 
 While the role of microtubule associated proteins (MAPs) has been speculated to be likely involved in taxane response, no studies have been initiated to rigorously test this hypothesis. Our project, for the first time, will dissect the mechanism of action of MAPs and definitively determine whether there is a causal relationship between their altered levels/activity and resistance to taxanes.