The largest analysis of breast cancer cell function to date has suggested dozens of new uses for existing drugs, new targets for drug discovery, and new drug combinations. The results of the study, which was conducted by researchers in New York City and Toronto, were published online in Cell.
“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 lead author Benjamin Neel, MD, PhD, director of New York University’s Perlmutter Cancer Center.
The researchers performed RNA screens on 77 breast cancer cell lines, a large enough sample to represent the many subtypes of the disease. The team then applied their newly designed statistical technique, the si/shRNA mixed-effect model (siMEM), to identify candidate genes most vital to cancer growth. They also compared their results against information in large databases on cancer genetics, protein interactions, and genetic changes seen in cancer cells when drugs are effective or not.
New and potentially “druggable” targets identified for triple-negative breast cancer, the most deadly form of the disease, included signaling proteins linked by past studies to brain tumors (EFNB3 and EPHA4), proteins that regulate cell-growth pathways (MAP2K4 and MAPK13), and a protein known to drive inflammation (interleukin 32).
The new data also identified dozens of potential drug combinations for the treatment of breast cancer subtypes, including RAF/MEK protein and cyclin-dependent kinase 4 (CDK4) inhibitors; epidermal growth factor receptor (EGFR) inhibitors and bromodomain and extra terminal domain (BET) inhibitors with epirubicin and vinorelbine; and polo-like kinase-1 (PLK1) inhibitors with AKT protein inhibitors.
While the researchers’ new statistical algorithm suggested pathways for further study in every breast cancer subtype, the team chose one for additional analysis to demonstrate the potential of their work to guide further research. Additional experiments validated BRD4 as a gene essential to the survival of most luminal/human epidermal growth factor receptor-2 (HER2)-positive cancer cells, as well as a subset of triple-negative breast cancer cells.
BRD4 is a member of the BET family, which helps regulate many genes important for cell growth, and is the target of BET inhibitors, currently in clinical trials for leukemia. The study results suggested that BET inhibitors might also be useful for some types of breast cancer; that resistance to these drugs may be influenced by mutations in the gene for the enzyme phosphatidylinositol 3-kinase; and that this resistance might be countered by combining BET inhibitors with everolimus (Afinitor, Novartis).
“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,” Neel said. “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.”
Source: NYU Langone Medical Center; January 14, 2016.