In Vivo Targeting Replication Protein A for Cancer Therapy.

Pamela S Vandervere-Carozza,Shadia I Jalal,John J Turchi,Steve M Patrick,Navnath S Gavande,Andi Masters,Joshua Heyza,Katherine S Pawelczak,Elmira Ekinci,Karen E Pollok

doi:10.3389/fonc.2022.826655

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 (RPAis) that block the RPA–DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 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 RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers.

Highlights

The DNA damage response (DDR) is composed of a complex network of DNA repair and cell signaling pathways that are critical toward maintaining genomic stability
As lung epithelial cells are continuously exposed to a wide array of potentially carcinogenic agents, a situation exacerbated by smoking and second-hand smoke exposure
The DDR is actively being pursued for cancer therapy, with phase I results being recently reported for ATR inhibitor (ATRi) [15]

Summary

Introduction

The DNA damage response (DDR) is composed of a complex network of DNA repair and cell signaling pathways that are critical toward maintaining genomic stability. Dysfunctional DDR causes damage to the genome that results in genomic instability, providing a selective advantage over normal cells and enabling rampant proliferation and survival. This genomic instability frequently arises from mutations of certain cell cycle and DDR genes, which in turn creates an increased dependency on other components of the DDR network. This reliance on specific DDR machinery can make cancer cells more vulnerable to therapies targeting DDR components. Other agents targeting specific DDR signaling molecules have shown singleagent and combination activity [3]

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Conclusion