Final Report Summary - TRIPLE-BC (Identification and functional validation of drugable targets/pathways for triple negative breast cancer)
Patients suffering from triple-negative breast cancer (TNBC), accounting 15-25% of breast cancer cases, have a poor prognosis as these tumors frequently confer resistance against chemotherapeutic agents, and lack the known drug targets estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor-2 (HER-2). Insufficient knowledge on the tumor biology of this specific breast tumor type hinders the identification of potential novel drug targets. In this ERC project Triple-BC, by using advanced bioinformatic approaches, and large scale RNA interference and kinase inhibitor screening, we have identified potential suitable drug targets and established and validated effective combination therapies of currently available and newly developed drugs that result in synergistic TNBC cell death in vitro. The most effective drug combination, involving drugs abolishing the function of epidermal growth factor receptor-1 (EGFR) and cyclin-dependent kinases (CDK) have functionally been investigated. Transcriptomic profiling revealed marked down regulation of pathways governing proliferation, transcription and cell survival in TNBC cells treated with the drug combination. In mice, the most promising combination therapy was well tolerated at dosages considered necessary to result in synergistic cell death. A number of genes enriched in the down-regulated pathways were found to be associated with poor prognosis in patients with TNBC. Ultimately, it is expected that the established newly designed (combination) therapies will result in a decline in TNBC mortality and a reduction in costs of healthcare.