Abstract 3681: RAD51AP1 is a novel therapeutic target for cancer prevention and treatment (2019)

Abstract Although much progress has been made in recent years in its treatment and prevention, cancer is still the second leading cause of death in the United States. Surgical removal of the tumor is not possible in all cancer types; therefore, chemotherapy and radiation therapy have become the standard course of treatment and are often the only option for more late stage and metastatic tumors. Unfortunately, chemotherapy and radiation therapy resistance are the greatest challenge for physicians trying to eradicate disease, prevent tumor recurrence, and inhibit distant metastasis. This resistance is derived from a heterogeneous population of cells within the tumor known as cancer stem cells (CSCs). CSCs are able to maintain a higher capacity for self-renewal due to a more efficient DNA repair system. CSCs are actively cycling, therefore, the repair mechanism of homologous recombination (HR) plays a significant role in repairing double-stranded DNA breaks that inevitably accumulate. Several studies have examined the link between efficient DNA repair and CSC self-renewal and found that proteins involved in HR repair are elevated in many human cancers. RAD51-associated protein 1 (RAD51AP1), which is responsible for the successful resolution of HR during DNA repair, is overexpressed in wide variety of human cancers. The present study sought to determine the functional role of RAD51AP1 in CSC self-renewal and its relevance to cancer growth and progression and also drug resistance. Our studies provide evidence that RAD51AP1 plays a critical role in CSC self-renewal and maintenance in breast, lung, and colon cancers. To determine the functional role of RAD51AP1 in cancer growth and progression, we generated genetically engineered mouse (GEM) models in breast and lung in WT (Rad51ap1+/+) and Rad51ap1-knockout (KO, Rad51ap1-/-) background and found that Rad51ap1 deletion significantly delayed the time of tumor formation and distant metastasis, which in turn increase the overall survival. Rad51ap1 inactivation in human breast and lung cancer cell lines, significantly reduced tumor growth in xenograft mouse model. This findings are also recapitulated in mouse mammary tumor cell lines (AT3 and 4T1). We also investigated the functional role of RAD51AP1 on colon cancer growth and progression using AOM/DSS and Apcmin/+ models of colon cancer and found that smaller tumor burden in KO mice compared to WT suggesting that Rad51ap1 may have a significant role in tumor growth. Taken together, these data demonstrate that RAD51AP1 plays a critical role in CSC growth and self-renewal in many human cancers and RAD51AP1 could be a novel therapeutic target for cancer prevention and treatment. Citation Format: Allison E. Bridges, Pragya Rajpurohit, Parth Patel, Nagendra Singh, Putter D. Prasad, Muthusamy Thangaraju. RAD51AP1 is a novel therapeutic target for cancer prevention and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3681.