Targeted therapies are designed to inhibit specific pathways driving the malignant phenotype while concurrently decreasing side effects on normal cells. However, very frequently, inhibition of the targeted pathway activates compensatory mechanisms designed to bring the pathway back into equilibrium allowing for cancer cell survival, a mechanism known as adaptive drug resistance. The purpose of this project is to identify and abrogate the adaptive drug resistance of epithelial cancers to rapamycin, an allosteric inhibitor of mTOR (mammalian target of rapamycin), and to rapamycin analogs in the PI3K (phosphoinositide-3-kinase) pathway, the most commonly dysregulated pathway in epithelial cancers. Using 3D- cultures, rapamycin-induced morphology changes and cell death were recorded. Changes in protein levels due to rapamycin-induced adaptive signaling were detected using reverse phase protein arrays (RPPA), verified by western blotting, and analyzed to determine potential adaptive mechanisms. Based on screening results from RPPA, rapamycin was combined with rationally selected drugs designed to thwart adaptive drug resistance to rapamycin. This co-extinction approach reinforced rapamycin into an effective inducer of cell death, ultimately bypassing drug resistance mechanisms and precluding the emergence of future therapeutic resistance. Successful combinations will be forwarded into animal studies to demonstrate in vivo efficacy for the treatment of epithelial cancers.

Note: This abstract was not presented at the meeting.

Citation Format: Moez Dawood, Yiling Lu, Gordon Mills. Identifying rational combination therapies with rapamycin for the treatment of epithelial cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3766. doi:10.1158/1538-7445.AM2015-3766