Abstract LB-B04: Complex drug combinations can induce apoptotic killing in robust colorectal cancer cells

Tumors are complex and robust biological systems that harbor the potential to proliferate against various drug treatments. Drug combinations provide a promising therapeutic strategy, but it is not clear which and how many drugs are required to overcome cancers. Using image-based proliferation and apoptosis assays in colorectal cancer cells we systematically investigated complex treatments composed of two to six drugs targeting critical oncogenic pathways. Drug pairs targeting growth signaling resulted in synergies across a broad spectrum of genetic backgrounds, but often yielded cytostatic responses and failed to induce apoptosis. Enhanced, and sometimes genotype-specific cytotoxicity was seen after targeting additional mechanisms including apoptosis or cell cycle. Cells that resisted all tested drug pairs and drug triples were protected by a mechanism that prevented apoptosis. Targeted inhibition of this mechanism using combinations of up to four compounds induced cytotoxic responses in cells in vitro and in vivo. Our results demonstrate that complex combinations of targeted drugs might be required to induce killing in cancers and show how the cells9 genetic alterations and a molecular understanding of drug responses can guide their identification. The identification of resistance mechanisms that are pre-existing in subpopulations of tumor cells also opens the exciting avenue of sequenced treatments, with each drug or drug combination targeting and eradicating a specific cell population. Citation Format: Thomas Horn, Stephane Ferretti, Nicolas Ebel, Angela Tam, Samuel Ho, Fred Harbinski, Ali Farsidjani, Matthew Zubrowski, Ensar Halilovic, Erick Morris, William R. Sellers, Robert Schlegel, Jens Wuerthner, Levi A. Garraway, Sebastien Jeay, Joel Greshock, Giordano Caponigro, Joseph Lehar. Complex drug combinations can induce apoptotic killing in robust colorectal cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B04.