Abstract S3-8: Identification of Novel Synthetic-Lethal Targets for MYC-Driven Triple-Negative Breast Cancer

Abstract

Abstract Currently, the greatest clinical challenge in treating breast cancer occurs in those patients whose tumors lack expression of the estrogen and progesterone receptors and the HER2 oncoprotein. No targeted agents currently exist against this aggressive type of receptor ‘triple negative’ breast cancer that disproportionately affects young African American women and also a substantial number of white American women. We have discovered that triple-negative tumors frequently express high levels of the MYC proto-oncogene. We sought to identify new “synthetic-lethal” strategies to selectively kill triple-negative breast tumors with MYC overexpression. Synthetic lethality arises when a combination of mutations in two or more genes leads to cell death, whereas a mutation in only one of these genes has little effect. Using this strategy, we can take advantage of the elevated MYC signaling in triple-negative tumors to selectively kill them, while sparing normal tissues in which MYC is expressed at much lower levels. RESULTS: We performed a shRNA synthetic-lethal screen to identify new molecules, such as cell cycle kinases, which when inhibited can preferentially kill triple-negative breast tumor cells. The unbiased shRNA-based screening approach was performed in human mammary epithelial cells (HMECs) that have inducible MYC over-expression. A high-throughput screen of ∼2000 shRNAs, that target the human kinome (∼ 600 kinases) was performed, and identified 13 kinases whose inhibition by >1 shRNAs gave rise to >50% inhibition of cell growth. Two of the kinases identified in our screen, ARK5 and GSK3A, were also recently identified by other studies and shown to have a synthetic-lethal interaction with MYC. These results validated our ability to identify synthetic-lethal targets. We are currently characterizing and validating the 11 novel targets identified in this screen, using human cancer cell lines as well as mouse cancer models to determine the impact of inhibiting these targets on triple-negative breast cancer development and proliferation. Additional synthetic-lethal interactions with MYC over-expression in triple-negative breast cancers will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S3-8.