Modeling resistance to pathway-targeted therapy in ovarian cancer.

A detailed understanding of the biochemical pathways that are responsible for cancer initiation and maintenance is critical to designing targeted cancer therapy. Although we have accumulated knowledge about individual molecular changes that underlie cancer development, we are still learning how multiple biochemical pathways cooperate in cancer. This cooperation and cross-talk between redundant biochemical pathways appear to be the main reasons for the failure of therapeutic agents that are designed to interfere with a specific molecular target. In order to simulate the cooperation of several biochemical pathways in cancer development, we have engineered mouse ovarian cancer cell lines and tumors with different combinations of defined genetic alterations. We have used this system to determine the functional contributions of individual pathways that are necessary for cell proliferation and tumor maintenance, as well as to test the molecular mechanisms of tumor resistance to pathway-targeted therapy.