Abstract
Dysfunctional DNA repair with subsequent genome instability and high mutational burden represents a major hallmark of cancer. In established malignant tumors, increased DNA repair capacity mediates resistance to DNA-damaging therapeutics, including cytotoxic drugs, radiotherapy, and selected small molecules including inhibitors of poly (ADP-ribose) polymerase (PARP), Ataxia Telangiectasia Mutated (ATM), ataxia telangiectasia and Rad3-related protein (ATR), and Wee1 kinase (Wee1). In addition, DNA repair deficiency is not only associated with sensitivity to selected anticancer drugs, but also with increased mutagenicity and increased neoantigen load on tumor cells, resulting in increased immunogenicity and improved response to CTLA4- or PD-(L)1 targeting monoclonal antibodies. DNA damage response (DDR) is composed of complex signalling pathways, including the sensing of the DNA damage, signal transduction, cellular response pathways to DNA damage, and activation of DNA repair. DNA double strand breaks (DSBs) are the most dangerous form of DNA damage. Tumor cells are characterised by frequent accumulation of DSBs caused by either endogenous replication stress or the impact of cancer treatment, most prominently chemotherapy and radiotherapy. Therefore, response of cancer cells to DSBs represents a crucial mechanism for how tumors respond to systemic treatment or radiotherapy, and how resistance develops. Ample clinical evidence supports the importance of DDR associated kinases as predictive and prognostic biomarkers in cancer patients. The ATM-CHK2 and ATR-CHK1-WEE1 pathways initiate DNA DSB repair. In the current review, we focus on major DDR associated kinases including ATM, ATR, CHK1, CHK2, and WEE1, and discuss their potential prognostic and predictive value in solid malignancies.
Highlights
Specialty section: This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology
We focus on major DNA damage response (DDR) associated kinases including Ataxia Telangiectasia Mutated (ATM), ATR, CHK1, CHK2, and WEE1, and discuss their potential prognostic and predictive value in solid malignancies
It has been shown that inhibition of WEE1 impairs homologous recombination (HR)-mediated DNA repair through activation of CDK1 and subsequent inhibitory phosphorylation of BRCA2 [15]
Summary
Beggs et al [41] Lim et al [44] Roossink et al [47] Kim et al [42] Kim et al [42]. N.A. According to TCGA pan cancer studies [23], the most frequent genetic alterations of CHEK1 is deep deletion, which is most commonly found in testicular germ cell tumors (~8.7%) and uveal melanoma (5%). CHEK1 point mutations are most frequently found in endometrial cancer (~3.8%) and in lung squamous-cell carcinoma (~2.1). Lee et al found CHK2 protein loss in 14.1% of patients with advanced gastric cancer and CHK2 loss was significantly associated with advanced TNM stage and poor DFS (HR = 1.970 95%CI:1.245–3.116, p < 0.001). Quantitative studies revealed significantly lower p-CHK2 expression in early stages of colorectal carcinomas compared to advanced stages. The authors found CHK2 protein to be more frequently expressed in patients with rare tumors and TABLE 2 | Studies examining prognostic and/or predictive value of ATR, CHK1, CHK2, and WEE1 in solid malignancies
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