Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy

Abstract

Proliferating cells regularly experience replication stress caused by spontaneous DNA damage that results from endogenous reactive oxygen species (ROS), DNA sequences that can assume secondary and tertiary structures, and collisions between opposing transcription and replication machineries. Cancer cells face additional replication stress, including oncogenic stress that results from the dysregulation of fork progression and origin firing, and from DNA damage induced by radiotherapy and most cancer chemotherapeutic agents. Cells respond to such stress by activating a complex network of sensor, signaling and effector pathways that protect genome integrity. These responses include slowing or stopping active replication forks, protecting stalled replication forks from collapse, preventing late origin replication firing, stimulating DNA repair pathways that promote the repair and restart of stalled or collapsed replication forks, and activating dormant origins to rescue adjacent stressed forks. Currently, most cancer patients are treated with genotoxic chemotherapeutics and/or ionizing radiation, and cancer cells can gain resistance to the resulting replication stress by activating pro-survival replication stress pathways. Thus, there has been substantial effort to develop small molecule inhibitors of key replication stress proteins to enhance tumor cell killing by these agents. Replication stress targets include ATR, the master kinase that regulates both normal replication and replication stress responses; the downstream signaling kinase Chk1; nucleases that process stressed replication forks (MUS81, EEPD1, Metnase); the homologous recombination catalyst RAD51; and other factors including ATM, DNA-PKcs, and PARP1. This review provides an overview of replication stress response pathways and discusses recent pre-clinical studies and clinical trials aimed at improving cancer therapy by targeting replication stress response factors.

Prognostic Assessment of Oxidative Stress-Related Genes in Colorectal Cancer and New Insights into Tumor Immunity

“…Oxidative DNA damage has been widely accepted as an important feature of the occurrence of malignant tumors. At present, researchers have found a variety of novel treatment methods based on ROS to restore chemoresistance and overcome radiotherapy resistance, enhance the efficacy of chemoradiotherapy, [27][28][29][30][31] and bring certain guiding significance to clinical treatment. At the same time, oxidative stress products in the tumor microenvironment also affect the immune response of the body.…”

Advances in Ovarian Cancer Care and Unmet Treatment Needs for Patients With Platinum Resistance

“…Replication stress is a targetable vulnerability in cancer cells owing to their mitotic rate as well as the loss of normal machinery to repair or prevent errors in DNA replication. 55 Ataxia telangiectasia and Rad3relatedprotein(ATR)andWEE1aremajorregulatorsofthecellularDNA damage response and are commonly upregulated by cancer cells to increase tolerance for replication stress. 56 Small-molecule inhibition of ATR or WEE1 sensitizes cells to chemotherapeutic agents, which increase replication stress.…”

The Multiple Faces of the MRN Complex: Roles in Medulloblastoma and Beyond

“…Indeed, MRN complex overexpression correlates with enhanced DDR and drug resistance in most cancers. Importantly, since several chemotherapy drugs induce RS [176,177], chemotherapy-treated and chemo-resistant cells could be considered automatically dependent on the MRN complex. In all these contexts, increasing evidence from in vitro and preclinical studies indicates that MRN complex targeting can be effective.…”