Abstract B48: Targeting SETD2 knockout cells: A synthetic lethal approach to treating ccRCC

Abstract

Background: Kidney cancer is estimated to affect 65,150 newly diagnosed individuals in 2013. Approximately 70% of these diagnoses will be clear cell renal cell carcinoma (ccRCC). Many targeted therapies for ccRCC are currently being pursued, as ccRCC is resistant to radiation and often does not respond to chemotherapy. The most commonly mutated tumor suppressor gene in ccRCC is VHL, located on chromosome 3. The loss of chromosome 3p is a high frequency event in ccRCC, which often also encompasses the genes PBRM1, BAP1, and SETD2. Mutations in one or more of these genes represent the next most common common genetic alterations in ccRCC. In our preliminary data, we have observed that mutations in SETD2, in particular, area associated with global deficits in chromatin packaging and organization.

Methods: We are pursuing the opportunity to exploit SETD2 loss as a source of cellular fragility by performing a small molecule screen on SETD2 wild type and SETD2 knockout cell lines. We will use a screening set of epigenetically targeted compounds to perform a high throughput screen with cell viability as the endpoint, as well as use a selected few compounds to compare effect on wild type and knockout cells in a more in depth manner.

Results: Preliminarily, we have tested SETD2 knock-down lines to confirm that we can effectively preform all aspects of this screen. In our current studies, we are repeating testing with the selected few compounds and beginning the high throughput screen with a SETD2 knockout cell line.

Conclusion: Mutations in chromatin modifying genes in ccRCC present an opportunity for synthetic therapeutic approaches to induce reduced cell viability, as well as to identify unique meaningful interactions between chromatin modifier genes.

Citation Format: Catherine C. Fahey, Kathryn E. Hacker, Jian Jin, Ian J. Davis, W. Kimryn Rathmell. Targeting SETD2 knockout cells: A synthetic lethal approach to treating ccRCC. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B48.