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Title: Targeting drug resistance in estrogen receptor positive breast cancer.
Host: Student/Postdoc Seminar Committee (Kyleen Castro)
Abstract: In 2021, 3.8 million women in the U.S. are either being treated or have finished treatment for breast cancer, and 43,600 women are expected to die from the disease. 70% of all breast cancer cases in women are estrogen receptor positive (ER+) and despite the success of antiestrogens in extending overall survival of patients, resistance to these therapies is prevalent. ER+ tumors that progress on antiestrogens are treated with combination of antiestrogens and CDK4/6 inhibitors. However, 20% of ER+ tumors never respond to CDK4/6 inhibitors due to de novo or intrinsic resistance. To address the molecular mechanisms underlying this type of resistance, we generated endocrine sensitive or resistant cells that are intrinsically resistant to CDK4/6inhibitors. Treatment with antiestrogens arrests cells in the G1 phase of the cell cycle, and therefore, we hypothesized that a defective G1 checkpoint allows resistant cells to escape this arrest and increases their dependency on G2 checkpoint for DNA repair and growth, and targeting the G2 checkpoint will induce cell death. Our data show that targeting crucial G2 checkpoint regulators is a promising anti-cancer therapeutic strategy in standard therapy resistant ER+ breast cancer.