Functional Genome-Wide Screening Identifies Triple-Negative Breast Cancer Cell Cycle-Dependent Vulnerability Driven By Genomic Gain Of Death Effector Domain-Containing Protein

Triple-negative breast cancer (TNBC) persists as a clinical challenge, with targeted therapeutic options remaining limited for the subtype due to few targetable tumor-specific vulnerabilities. While basal-like TNBC tumors express epidermal growth factor receptor (EGFR), the target of multiple clinically efficacious therapies, TNBC showed little to no response to anti-EGFR therapy in clinical trials. Using a genome-wide synthetic lethal pooled barcoded shRNA screen, we identified Death Effector Domain-containing protein (DEDD), upregulated in over 60% of TNBC tumors, as a driver of mitogen-independent G1/S cell cycle transition in TNBC under EGFR inhibition. This cell cycle role of DEDD depends on cytoplasmic localization and is independent of nuclear DEDD, which maintains roles in apoptosis. Cytosolic DEDD promotes G1/S transition through direct interaction with Rb family proteins, encouraging their degradation. Further, DEDD interacts with heat shock 71kDa protein 8 (HSC70) to augment cyclin D1 expression and drive transition to S phase. These interactions of overexpressed cytosolic DEDD with the G1/S checkpoint mechanism present a vulnerability of TNBC to cell cycle inhibition. Frequent Rb-loss in TNBC has prevented clinical testing of CDK4/6 inhibitors in TNBC, however. Yet, we found TNBC with DEDD overexpression to be sensitive to a combination of CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo, independent of Rb status. This novel vulnerability presented by DEDD overexpression in TNBC suggests promising therapeutic potential for CDK4/6 inhibitor use in combinatorial regimens. Citation Format: Yingjia Ni, Keon R. Schmidt, Barnes A. Werner, Jenna K. Koenig, Ian H. Guldner, Patricia M. Schnepp, Xuejuan Tan, Lan Jiang, Misha Host, Longhua Sun, Erin N. Howe, Junmin Wu, Laurie E. Littlepage, Harikrishna Nakshatri, Siyuan Zhang. Functional genome-wide screening identifies triple-negative breast cancer cell cycle-dependent vulnerability driven by genomic gain of death effector domain-containing protein [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4841.