Uncovering a Non-Canonical Role of ATR Kinase in Tumor Hypoxia for Safer Breast Cancer Therapy

Triple-negative breast cancer (TNBC) is an aggressive subtype associated with poor prognosis and disproportionately affects Black women. Hypoxia is a defining feature of TNBC and drives treatment resistance and high recurrence rates despite intensive chemo- and radiotherapy. Despite the clinical significance of hypoxia, previous unsuccessful hypoxia-targeted therapies have largely employed cytotoxic compounds lacking hypoxia-specific biological effects. Given the stress-adaptive nature of hypoxic cancer cells, a more rational strategy is to target critical hypoxia-adaptive mechanisms essential for their survival. My research has uncovered a novel, non-canonical ATR kinase–regulated mechanism critical to the survival of hypoxic TNBC cells. The proposed activities during this award aim to elucidate the molecular basis of this mechanism and develop a new class of hypoxia-targeted therapies with improved safety and selectivity, while also enhancing my research profile through collaborative networking, research entrepreneurship, and bioinformatics training. By integrating cutting-edge science with structured career development, this award will better position me to establish an inclusive, translational cancer research program focused on improving outcomes for underrepresented communities and addressing the disparities affecting Black populations in cancer research, despite the disproportionately high cancer burden they face. Keywords: Triple-negative breast cancer, hypoxia, ATR kinase, Black women, Autophagy