Over the last decade, comprehensive sequencing studies have mapped the genomic landscapes of common forms of malignant diseases. These efforts have identified the genomic alterations of the predominant oncogenes and tumors suppressor genes that consequence with a hyperactivity of survival pathways and unregulated proliferation of tumor cells. Molecular targeted therapies designed to interact with their target to block the activity of the survival pathways. Precision medicine using targeted therapy is a promising approach of treatment because the genomic profile of an individual can be used to predict responsiveness to certain agents, and allows an independent treatment plan to be designed for each patient. However, its potential has been limited by the development of resistance to targeted therapies. Resistance to anti-cancer therapies is attributed to intrinsic mechanisms (cell autonomous) or extrinsic mechanisms (mediated by cells in the tumor microenvironment) that limit the efficacy of therapy. Our goal is to investigate the intrinsic and extrinsic molecular mechanisms by which tumor cells overcome inhibition of the PI3K/AKT and EGFR pathways. These studies will provide fundamental insight into the evolution of resistance acquisition.