I want to design an experiment that measures acquired drug resistance and I need few guidelines.

What is the general way to do this? Particularly speaking this is for cancer treatment and I want to find out if a particular drug is causing acquired resistance after a period of treatment. I need few guidelines.

What type of samples do I need? From what? Can cell lines be useful? What things should be measured? For example, can gene expression or mutation measurements be useful? How can I measure mutation, in case it is useful? Would a clinical trial at the end be desired to validate the hypothesis or a mathematical model would suffice?

Any help or feedback would be highly appreciated.