Unveiling new molecular mechanisms of therapy-induced adaptive resistance in triple negative breast cancer.

The development of drug resistance, the prime cause of failure in triple negative breast cancer (TNBC) therapy, is the biggest hurdle to overcome in order to increase overall and disease free-survival rates. Recent findings indicated that, upon therapy, cells acquired drug resistance by transcriptome reprogramming rather than de novo acquisition of resistance-inducing mutations. However, the mechanisms initiating non-mutational acquired drug resistance and how to prevent it remain unknown. Identification of the molecular mechanisms of acquired resistance and characterization of the drugtolerant subpopulation(s) may allow their selective prevention before stable resistance is established. Using paired (therapy treated vs. untreated) TNBC human samples, patient derived xenografts (PDX) and TNBC cell lines we identified new drug tolerant state which correlates with Wnt pathway upregulation and expression of stem cell markers. We hypothesize that early induction of canonical Wnt pathway upon chemotherapy and its maintenance is a pivotal step in the acquisition of drug-resistance in TNBC. The enclosed proposal, aims at gaining insights into the biology of drug tolerant subpopulation and establishing its contribution to acquired drug resistance. Our research might provide a proof of concept to design more efficient pharmacological regimens by specifically targeting this particular drug-tolerant state during chemotherapy treatment.