Dozens of new uses for existing drugs, new targets for drug discovery, and new drug combinations have been suggested by the largest analysis of breast cancer cell function to date. The study, published in Cell (doi:10.1016/j.cell.2015.11.062), is also expected to aid in identifying new drug candidates for other types of cancer.
“This study represents the largest survey yet of how the genetic changes in breast cancer cells interfere with pathways critical to their growth and survival, pathways that might be targeted by combinations of new or existing drugs” said Benjamin Neel, MD, PhD, of the Princess Margaret Cancer Center in Toronto, Ontario, and the Perlmutter Cancer Center at New York University Langone Medical Center in New York City, and lead author of the study.
The research team screened 77 breast cancer cell lines using an algorithm they developed to better identify context-dependent genes. Combining the algorithm with detailed information on the genome and proteome (proteins expressed in the cells), the researchers identified potential drivers of breast cancer.
The usefulness of this approach was demonstrated by identifying BRD4 as essential for luminal cancer, and thus a potential therapeutic target, and by identifying that BET-inhibitor resistance is conferred by mutant PIK3CA. Resistance to BET inhibitors might be overcome through combinations with everolimus.
Several therapeutic targets were found for triple-negative breast cancer, including signaling proteins linked by past studies to brain tumors (EFNB3 and EPHA4), proteins that regulate cell growth pathways (MAP2K4, MAPK13), and a protein known to drive inflammation (interleukin 32).
Dozens of new, potential drug combinations were suggested by the data, including RAF/MEK and CDK4 inhibitors, EGFR inhibitors and BET-inhibitors with epirubicin and vinorelbine, and PLK1 inhibitors with AKT inhibitors.
“Very few patients today get a whole genome sequence analysis done on their cancer cells, and the few that do typically receive little medical benefit from the results,” said Neel. “The ultimate goal of researchers worldwide is to finally understand each cancer cell’s wiring diagram well enough to clarify both the molecular targets against which therapeutics should be developed and the patient groups most likely to respond to any treatment.”