Gene expression profiling of Triple Negative Breast Cancer MB157 cells and GSI-resistant MB157R cells upon induction of Notch1 or Sox2 signaling.

Cell plasticity of Triple negative breast cancer (TNBC) contributes to tumor heterogeneity and is one of the major reasons for the limited success of chemo- or combination therapies in the clinics. The molecular mechanisms of therapy-induced tumor cell plasticity and associated resistance to chemo or targeted therapies are largely unknown. Using a genome wide CRISPR-Cas9 screen we investigated the escape mechanisms of Notch driven TNBC, when treated with targeted therapy. We describe molecularly a reciprocal inhibitory feedback mechanism between Notch signaling and the pluripotency associated transcription factor SOX2, which shapes divergent cell states, EMT, cancer stem cell features and associates with therapeutic response and escape to targeted therapy. Moreover, we performed and assessed monotherapy and drug combination treatments in Notch-inhibitor sensitive and resistant TNBC xenotransplant and identified combination and second line treatment options which were able to induce tumor control and reduce metastatic burden.