Abstract
DNA damage response (DDR) is critical to ensure genome stability, and defects in this signaling pathway are highly associated with carcinogenesis and tumor progression. Nevertheless, this also provides therapeutic opportunities, as cells with defective DDR signaling are directed to rely on compensatory survival pathways, and these vulnerabilities have been exploited for anticancer treatments. Following the impressive success of PARP inhibitors in the treatment of BRCA-mutated breast and ovarian cancers, extensive research has been conducted toward the development of pharmacologic inhibitors of the key components of the DDR signaling pathway. In this review, we discuss the key elements of the DDR pathway and how these molecular components may serve as anticancer treatment targets. We also summarize the recent promising developments in the field of DDR pathway inhibitors, focusing on novel agents beyond PARP inhibitors. Furthermore, we discuss biomarker studies to identify target patients expected to derive maximal clinical benefits as well as combination strategies with other classes of anticancer agents to synergize and optimize the clinical benefits.
Highlights
The combination of Androgen receptor (AR) inhibition by enzalutamide (AR antagonist) and AZD7762 (CHK1/2 inhibitor) showed a synergistic effect in xenograft models of prostate cancer [161]. Based on these preclinical data, abiraterone was combined with olaparib or placebo in a randomized phase 2 trial in patients with metastatic castration-resistant prostate cancer; abiraterone plus olaparib was associated with a significant prolongation of progression-free survival (PFS) vs. abiraterone plus placebo (13.8 months vs. 8.2 months, respectively) [162]
Defects in DNA repair are abundant in cancer cells, offering an opportunity to exploit these alterations for clinical benefit
The molecular mechanisms of DNA damage response (DDR) have been an active area of scientific research for several decades, there remains more to understand in order to exploit this pathway as a therapeutic target
Summary
DNA damage response (DDR) pathways meticulously restore damaged sequences or direct irreparably damaged cells to undergo apoptosis or senescence. Genomic instability is an important hallmark of cancer, and defects in the DDR pathway may promote the growth of cancer cells by inducing de novo driver mutations, generating tumor heterogeneity, and evading apoptosis [1,5,6]. As the pharmacologic blockade of the DDR signaling cascade directs tumor cells to rely on compensatory survival pathways, these vulnerabilities have been exploited in anticancer therapies [6]. The use of PARP inhibitors in BRCA-mutated cancers represents a successful example of this strategy, and more recently, the development of potent and selective agents that target DDR signaling components is rapidly emerging as a promising therapeutic option. We discuss the recent development of promising new agents that target the DDR pathway, biomarker studies to patient cohorts that are expected to derive clinical benefits from their use, and ongoing preclinical and clinical investigations to optimize these strategies
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