Mechanisms of Targeting Triple-Negative Breast Cancer Genomic Vulnerability
Technical Report,01 Sep 2018,31 Aug 2019
UNIVERSITY OF NOTRE DAME Notre Dame United States
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Triple-negative breast cancer TNBC is the most aggressive type of breast cancer. Due to genome complexity, there is a lack of targeted therapies for TNBC. In this DoD project, we aim to address two identify molecular mechanisms that drive TNBC progress. Defining the genomic vulnerability of TNBC will also help us and design novel combinatorial therapies for TNBC patients. In this first funding year, we have conducted extensive in vitro and in vivo studies to define the mechanisms of TNBC progression. We validated our preliminary synthetical lethal screening results and demonstrated that DEDD overexpression leads to accelerated G1-S cell cycle transition. Mechanistically, DEDD interacts with HSC70 and promote Rb degradation. We further demonstrated that DEDD could be exploited as a targetable vulnerability of TNBC. Combinatorial treatment of lapatinib and CDK46 inhibitor synergistically suppressive TNBC tumors.
- Medicine and Medical Research