Functional Screen Identifies Triple-Negative Breast CancerVulnerability Driven by Death Effector Domain-ContainingProtein

Identifying targetable and cancer-specific vulnerability is a prerequisite to the development of novel personalized cancer therapies. Lacking mechanistically-defined and targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically-challenging breast cancer subtypes. In this study, through a genome-wide synthetic lethal RNAi screen, we revealed Death Effector Domain-containing DNA-binding protein (DEDD) drives a mitogen-independent G1/S cell cycle transition in TNBCs, independent to DEDD’s pro-apoptotic functions in the nucleus. Overexpressed in >60% TNBC tumors, cytosolic DEDD facilitates an accelerated cell cycle progression and renders TNBC cells vulnerable to cell cycle inhibition. Mechanically, the gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock protein HSC70. Concurrently, DEDD interacts with tumor suppressor Rb family proteins and promotes their proteasome-mediated degradation, further contributing to the accelerated G1/S cell cycle progression. Clinically, despite the successes of cyclin D kinase CDK 4/6 inhibitors in breast cancer, TNBC patients have been excluded from CDK 4/6 inhibitors clinical trials due to the perceived high frequency of Rb loss. Contrary to this prevailing notion, my study demonstrated that, regardless of Rb status, TNBCs with DEDD overexpression exhibit a DEDD-dependent vulnerability to the combinatorial treatment of CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Taken together, my study revealed a TNBC-specific vulnerability conferred by DEDD-driven dysregulated cell cycle progression and provided a rationale for the clinical application of CDK4/6 inhibitor containing combinatorial regimens for TNBC patients.