Abstract
Simple SummaryChemotherapeutic DNA-damaging agents targeting replication are widely used but predictive rationales for drug combinations and patient selection still need clinical definition. Here, we review cancer-associated replication stress (RepStress) and its genomic signature, and propose how to utilize RepStress-targeted therapies in the context of ATR inhibitors and Schlafen 11 (SLFN11).Precision medicine aims to implement strategies based on the molecular features of tumors and optimized drug delivery to improve cancer diagnosis and treatment. DNA replication is a logical approach because it can be targeted by a broad range of anticancer drugs that are both clinically approved and in development. These drugs increase deleterious replication stress (RepStress); however, how to selectively target and identify the tumors with specific molecular characteristics are unmet clinical needs. Here, we provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker.
Highlights
Accepted: 9 September 2021Targeting the genome and DNA replication were the first approaches to the chemical treatment of cancers
Understanding the DNA replication-targeted agents and DNA damage response (DDR) is required for providing biomarkers (Figure 2) that can be utilized for selecting patients who should benefit from targeted therapies
Only a small subset of replication origins is licensed by the loading of the six-subunit origin recognition complex (ORC), the cell division cycle 6 (CDC6), the chromatin licensing, and DNA replication factor 1 (CDT1). This follows the recruitment of the replicative DNA helicase minichromosome maintenance complex 2-7 (MCM2-7) as the pre-replicative complex that remains in an inactive state prior to S-phase
Summary
Targeting the genome and DNA replication were the first approaches to the chemical treatment of cancers. DNA topoisomerase (TOP) inhibitors were discovered as potent anticancer agents prior to the elucidation of their molecular mechanism of action by selectively trapping of the TOP cleavage complexes (TOPcc) by interfacial inhibition [1,2,3]. The selection of patients according to the expression of Schlafen 11 (SLFN11) has recently been reported to be correlated with improved response in several human cancer types [9,10,11]. We review precision medicine in the context of RepStress-targeted agents, which primarily act by interfering with DNA replication. Tients according to the expression of Schlafen 11 (SLFN11) has recently been reported to be correlated with improved response in several human cancer types [9,10,11]. We summarize key molecular of DNA replication and discuss to exploit.
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