Modeling resistance to pathway-targeted therapy in ovarian cancer

Abstract

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.

Figure 1

Epithelial-mesenchymal transition is induced by the MEK/ERK signaling pathway in mouse ovarian carcinoma cells. The T22 mouse ovarian carcinoma cell line was engineered to contain genetic alterations in the p53, c-myc and Akt oncogenes. The T22 cells have an epithelial morphology and accumulate crystal violet dye. The introduction of oncogenic H-ras into the T22 cells results in epithelial-mesenchymal transition and a reduced accumulation of crystal-violet dye. Treatment of the T22+H-ras cells with vehicle or 100 ng/ml rapamycin for 48 hours does not change the mesenchymal morphology of the cells. However, the mesenchymal cells revert to an epithelial morphology upon treatment with 50 μM of the MEK inhibitor PD98059.

Figure 2

Oncogenic H-ras signaling contributes to the phosphorylation of the 4E-BP1 protein and the accumulation of the cyclin D1 and p21 proteins. These effects cannot be reversed by rapamycin treatment.