Overcoming chemoresistance in triple negative breast cancer by bromodomain inhibition

Background: Triple negative breast cancer (TNBC) is an aggressive subtype of with poor prognosis. TNBC cells do not express receptors for estrogen, progesterone or Her2, eliminating the possibility targeted therapy applications. Therefore, current treatment option limited surgery followed by conventional chemotherapy. However, acquired resistance to chemotherapy a major challenge that associated relapse, which driven coordinated actions genetic and epigenetic events. Materials Methods: We aimed elucidate roles full spectrum modifiers in maintenance reversion chemoresistance TNBC. To generate vitro models chemoresistant TNBC, we exposed 3 different cell lines escalating doses taxane (paclitaxel). Transcriptome analysis RNA-sequencing were performed reveal changes regulate chemoresistance. With our custom epigenome-wide CRISPR-Cas9 library (Epigenetic Knock-Out Library - EPIKOL) targeting all chromatin readers, writers, erasers proteins, systematically interrogated cells. also conducted medium scale chemical screens utilizing probe libraries Results: RNA sequencing on paired sensitive revealed ABCB1 upregulation as driver resistance. Inhibition members MLL SWI/SNF complexes, well genes related histone ubiquitination acetyl-mark readers re-sensitized paclitaxel. A member bromodomain protein family, BRPF1, came common hit screen screens. Knockout BRPF1 its inhibition completely abolished paclitaxel modulated expression. Conclusions: Through EPIKOL coupled screens, identified novel are crucial maintaining overcoming drug Collectively, these findings provide basis develop combination therapies efficiently kill Key words: Epigenetics, cancer, This work was supported The Scientific Technological Research Council Turkey (TUBITAK) 1003- 216S461 Grant No conflict interest.