Abstract 975: Employing functional genomics to reveal emergent dependencies

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Using a pangenomic loss of function strategy, our group has recently discovered that a cohort of gametogenic genes modulates chemoresponsiveness in tumor cells. Numerous studies focused on identifying aberrant gene expression patterns in tumors have previously correlated the presence of gametogenic genes with the tumorigenic state. Our functional genomics approach has now revealed that these tumor-activated aberrant gene products may play essential roles in supporting tumor cell fitness in the presence of insults, such as genotoxic stress. Specifically, depletion of each of the 8 gametogenic genes identified in our screen results in an increase in mitotic transit time and a reduction in mitotic fidelity in the presence of paclitaxel, demonstrating a requirement for their function at the level of chromosome segregation. At the cell biological level, these components contribute to mitotic spindle architecture by supporting centrosomal coalescence, centrosome duplication and/or microtubule stability. Given that the expression of these genes is otherwise biased towards the germline, they could present pharmacological entry points with an extraordinary therapeutic window. For example, we find that the CT-antigen, ACRBP, specifies poor outcome in ovarian patients and depletion of ACRBP can enhance sensitivity to paclitaxel in ovarian tumor explants in vitro and an ovarian orthtopic xenografts in vivo. In addition, we find that a small molecule that targets the gametogenic protein, TACC3, synergizes with paclitaxel to reduce tumor cell growth. We propose that the dependency on these gametogenic components may arise as a consequence of passage through a selection bottleneck, during tumor evolution, which requires acquisition of traits that normalize the mitotic perturbations originally driving the plasticity of preneoplastic genomes. We show that such traits, when defined by otherwise anomalous gene products, may represent conceptually ideal intervention targets with wide therapeutic windows. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 975. doi:1538-7445.AM2012-975