Abstract P6-06-01: Comprehensive analysis of the DNA damage repair and maintenance pathways that regulate TNBC sensitivity to replication stress

Abstract

Abstract Agents that induce replication stress, such as inhibitors of Chk1 or ATR, are advancing in clinical development and are being tested for treatment of various solid tumors, including triple-negative breast cancer (TNBC). While the preclinical data are encouraging, additional studies are needed to predict with precision (i) which patients will most likely benefit from these inhibitors, (ii) the genetic and proteomic contexts in which these inhibitors will provide maximum therapeutic benefit as a single agent, or require additional sensitization via combination with a targeted- or chemotherapeutic agent, and (iii) exactly which targeted/chemotherapeutic agent will provide maximum therapeutic benefit for combination with replication stress inducers. To address these challenges in TNBC, we have attempted to gain a comprehensive understanding of how the DNA damage response pathways regulate TNBC cell survival in response to Chk1 inhibitors, by performing high throughput loss-of-function screens. We have identified genes whose loss induces death of TNBC cells in the presence of (1) CHK1i alone, (2) chemotherapy alone or (3) CHK1i plus chemotherapy. In addition, given the role of TP53 as the most frequently mutated gene in TNBC, we also determined whether distinct vulnerabilities could be identified in TNBC cells that are p53-proficient versus p53-deficient. Thus, we have also identified the top synthetic lethal interactions that are either common to both p53-proficient and p53-deficient TNBC, or unique to p53-deficient TNBC; we are currently performing in vitro studies to validate the identified mechanisms. We anticipate these studies to be applicable to other agents that induce replication stress and cell cycle checkpoint bypass. Ongoing in vivo preclinical studies, which utilize patient-derived xenografts (PDXs) of TNBC to validate these findings are expected to impact patient selection for clinical trials, and also allow us to predict which chemotherapeutic agents will be most effective for combination with different cell-cycle checkpoint inhibitors. Citation Format: Redwood AB, Seth S, Cai S, Piwnica-Worms H. Comprehensive analysis of the DNA damage repair and maintenance pathways that regulate TNBC sensitivity to replication stress [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-06-01.