Abstract B18: High-dimensional combinations of cancer drugs to induce synthetic lethality in colorectal cancer

Cancers are inherently robust biological systems with many compensation mechanisms and genetic redundancies allowing them to escape treatments and become resistant. Theoretically, such complex systems can become fragile when perturbed by multiple attacks. Here, we systematically tested whether pairwise combinations of compounds targeting critical oncogenic pathways in colorectal cancer cells can combine to inhibit their growth or even kill them. Some combinations targeting growth pathways showed synergies in a broad spectrum of genetic backgrounds even when the single agents had more specific effects. Guided by the pairwise combination screening, we identified higher-dimensional combinations that not only showed broad synergy but could also drive cytostatic combination responses into synthetic lethality. Citation Format: Thomas Horn, Xiaobin Zhang, Samuel Ho, Levi Garraway, Robert Schlegel, Giordano Caponigro, Joseph Lehar. High-dimensional combinations of cancer drugs to induce synthetic lethality in colorectal cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B18.