Abstract 808: In vivo targeting of replication protein A for cancer therapy

Abstract

Abstract Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination and the DNA-damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second generation RPA inhibitors (RPAi’s) that block the RPA-DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first generation RPAi’s, second generation molecules with increased cellular permeability, induce cell death via apoptosis. Second gen RPAi’s elicit single agent in vitro anticancer activity across a broad spectrum of cancers and the cellular response supports a threshold exists before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors as well as traditional DNA damaging cancer therapeutics. Consistent with the chemical RPA exhaustion model, we demonstrate that the effects of RPAi on replication fork dynamics. An optimized formulation was developed that resulted in single agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAi’s eliciting a state of chemical RPA exhaustion can provide an effective therapeutic option for difficult to treat lung cancers. Citation Format: Pamela VanderVere-Carozza, Navnath Gavande, Shadia Jalal, Karen Pollok, Elmira Ekinci, Joshua Heyza, Steve Patrick, Andi Masters, John Turchi, Katherine Pawelczak. In vivo targeting of replication protein A for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 808.