Abstract 2481: RAD51 and AICDA define a new synthetic lethal interaction that is targetable in multiple tumor types

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 13_Supplement; p. 2481
• Main Authors: Mills, Kevin D., Roche, Marly I., Cyr, Amber, Maclay, Tyler, Hasham, Muneer G., Lamont, Kristin, Branca, Jane, Cavallo, Francesca, Jasin, Maria, Stern, Alvin, Kwon, Youngho, Zhao, Weixing, Sung, Patrick
• Format: Journal Article
• Language: English
• Published: 01-07-2017
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-2481

Antigen stimulated B-cells transiently express Activation Induced Cytidine Deaminase (AID) which initiates point mutations and DNA double strand breaks (DSB) in immunoglobulin genes to promote B-cell maturation. However, AID is capable of broadly damaging the B-cell genome. We have shown that AID-induced DSBs require the homologous recombination factor RAD51 for their repair. Using genetic approaches, we discovered that reduced HR function is cytotoxic to AID-expressing B-cells. We subsequently demonstrated the feasibility of small molecule inhibition of RAD51 to sensitize AID-overexpressing tumor cells. Here we build on those observations, finding that AID-RAD51 synthetic lethality occurs via mitotic catastrophe, involving the mTOR pathway. We have now developed potent and selective RAD51 modulatory small molecules that preferentially kill AID-expressing tumor cells. Using mouse models of lymphoma and leukemia we provide in vivo efficacy data demonstrating the potential therapeutic feasibility of RAD51 modulation. These studies provide evidence for a novel “synthetic lethal” approach for treating AID-expressing malignancies, via the induction of mitotic catastrophe.
Citation Format: Kevin D. Mills, Marly I. Roche, Amber Cyr, Tyler Maclay, Muneer G. Hasham, Kristin Lamont, Jane Branca, Francesca Cavallo, Francesca Cavallo, Maria Jasin, Alvin Stern, Youngho Kwon, Weixing Zhao, Patrick Sung. RAD51 and AICDA define a new synthetic lethal interaction that is targetable in multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2481. doi:10.1158/1538-7445.AM2017-2481