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Nickoloff, J.A. Targeting Replication Stress Response Pathways to Treat Cancer. Encyclopedia. Available online: (accessed on 14 June 2024).
Nickoloff JA. Targeting Replication Stress Response Pathways to Treat Cancer. Encyclopedia. Available at: Accessed June 14, 2024.
Nickoloff, Jac A.. "Targeting Replication Stress Response Pathways to Treat Cancer" Encyclopedia, (accessed June 14, 2024).
Nickoloff, J.A. (2022, August 10). Targeting Replication Stress Response Pathways to Treat Cancer. In Encyclopedia.
Nickoloff, Jac A.. "Targeting Replication Stress Response Pathways to Treat Cancer." Encyclopedia. Web. 10 August, 2022.
Targeting Replication Stress Response Pathways to Treat Cancer

Proliferating cells regularly experience replication stress caused by spontaneous DNA damage that results from endogenous reactive oxygen species, DNA sequences that can assume secondary and tertiary structures, collisions between opposing transcription and replication machineries, and exogenous genotoxic agents. Replication stress often leads to DNA double-strand breaks (DSBs) that can cause genome instability and cell death. The importance of replication stress responses in cells exposed to genotoxic chemo- or radiotherapy has prompted considerable research focused on how tumor cells might be selectively killed by combined treatments with genotoxins and agents targeting DNA damage response (DDR) factors involved in the replication stress response.

DNA replication stress DNA damage response oncogenic stress

1. Targeting Downstream DNA Damage Checkpoint Factors (Chk1, Chk2, Wee1)

Many DDR targets along the DNA damage sensing-signaling-repair continuum have been explored as potential cancer therapeutic targets [1]. In the 1990s and early 2000s, there was considerable excitement about combining genotoxic chemo- or radiotherapy with inhibitors of checkpoint effector kinases. The general idea was that by inhibiting effector checkpoint kinases Chk1, Chk2, or Wee1, cells experiencing genotoxic stress would fail to arrest, and continued cell cycle progression in the face of significant DNA damage would lead to cell death by mitotic catastrophe or other mechanisms. This prompted the early development of Chk1 inhibitors (Chk1i) including UCN-01. Despite success in preclinical studies, in a Phase I trial, UCN-01 had a long half-life but limited bioavailability due to high avidity to plasma α1-acid glycoprotein, and serious side effects were observed when doses were increased to exceed the plasma binding capacity [2]. By 2013, at least 12 additional Chk1i were developed, but like UCN-01, many were cross-inhibitory with other targets (e.g., Chk2, CDK1, VEGFR2, PIM1) and only one, LY2603618, combined with the antifolate antineoplastic drug Pemetredex, reached a Phase I/II trial [3]. The severe side effects of UCN-01 may reflect the rather broad impact that Chk1 has on cellular functions, including replication initiation, replication fork stabilization, cell cycle progression, DNA repair, and apoptosis. Alternatively, the disappointing results with early Chk1i may reflect their lack of specificity.

2. Targeting the Upstream DNA Damage Checkpoint Kinase ATR and Its Activation Partner TopBP1

Given the propensity of serious side effects and limited clinical benefits to date for Chk1i, it may seem counterintuitive that targeting ATR, which acts upstream of Chk1, would have fewer adverse effects on normal tissues. Nevertheless, potent and relatively specific ATRi have been developed and several have been tested in mono- or combination therapy in Phase I/II trials. The ATRi BAY1895344 has shown promising results in a Phase I trial against advanced solid tumors, with ~20% of patients showing partial responses and nearly 40% showing stable disease. Although adverse effects with BAY1895344 were common, including hematologic problems, fatigue, and nausea, these were manageable [4]. The ATRi AZD6738 (Ceralasertib) was well tolerated in combination with carboplatin in a Phase I trial that also showed moderate clinical benefit [5]. Interestingly, in both of these ATRi trials, patients who responded had DDR defects, including loss of ATM. These results should motivate further studies with ATRi and other DNA damage checkpoint inhibitors in patients with DDR defects to further develop personalized therapies.
TopBP1 functions in a variety of cellular processes and has many binding partners [6], including itself, topoisomerase IIβ, p53, and RAD51 [7], and it plays a critical role in ATR signaling to Chk1 [8]. TopBP1 expression is frequently increased in osteosarcoma and other sarcomas, and this correlates with poor prognosis [9]. Interestingly, low or moderate levels of TopBP1 correlate with normal ATR/Chk1 activation during stress, but TopBP1 overexpression has an inhibitory effect on ATR/Chk1 activation [10], which, in theory, would promote the resistance of tumor cells to DNA damage by suppressing apoptosis. Because TopBP1 functions depend on protein–protein interactions, specific inhibitors that block these interactions are of interest. The cell viability dye calcein acetoxymethyl ester (calcein AM) was shown to interfere with TopBP1 oligomerization and p53 binding, resulting in the reactivation of apoptosis and interference with mutant/oncogenic p53 [11]. Calcein AM showed antitumor activity against breast cancer xenografts [11] and it increased the antitumor activity of the topoisomerase inhibitor doxorubicin against lung tumor xenografts [12]. To date no TopBP1 inhibitors have advanced to clinical trials.

3. Targeting Replication Stress Nucleases (CtIP, MUS81, EEPD1, Metnase)

Several nucleases play key roles in the replication stress response [13]. CtIP is a nuclease and key factor in the early steps of DNA end processing at DSBs, functioning with BRCA1 in both end resection to create single-stranded DNA (ssDNA) required for homologous recombination (HR) repair, and in the protection of stressed replication forks [14][15][16]. It thus plays an important role in creating the ssDNA-RPA substrate required for ATR activation [17]. A recent study demonstrated that a peptide mimic that blocks CtIP tetramerization is a specific CtIPi that impairs DSB repair, interferes with stressed fork protection, sensitizes cells to DNA damage and PARP1i, and is cytotoxic to BRCA1-defective cells [18]. CtIP is also a target of a lncRNA (lnc15.2)-encoded micropeptide termed PACMP. PACMP stabilizes CtIP by blocking its ubiquitination, and it also promotes poly(ADP)ribosylation of substrates by PARP1 [19]. siRNA knockdown of lnc15.2 causes hypersensitivity to PARP1i, ATRi, CDK4/6i, the TopoI inhibitor camptothecin, the TopoII inhibitor epirubicin, and radiation, and it has antitumor activity against breast tumor xenografts [19]. Together, these results warrant further studies to test the antitumor effects of CtIPi in preclinical and clinical trials.
Several nucleases that process stressed replication forks are being explored as therapeutic targets. MUS81 cleaves stalled replication forks to initiate HR-mediated fork restart [20], and it has shown promise as a target in preclinical studies [21][22]. EEPD1 also cleaves stalled replication forks [23][24] and given that MUS81 and EEPD1 cleave forks with different polarity [13], combining MUS81i and EEPD1i may be a potent approach to augment the cytotoxic effects of replication stress. Metnase is a nuclease and protein methylase that promotes replication fork restart, but it does not cleave stalled forks [23]. Metnase nuclease is inhibited by the frequently administered antibiotic Ciprofloxacin [25], suggesting a safe and potentially effective means to augment genotoxic cancer therapy, perhaps in combination with drugs targeting other DDR factors.

4. Targeting DSB Repair Proteins (RAD51, PARP1)

RAD51 plays a central role in HR repair of DSBs, and HR plays a critical role in fork protection and the accurate repair and restart of collapsed replication forks. RAD51 is frequently overexpressed in cancer cells [26], thus RAD51 has emerged as a potentially useful target in cancer therapy. RI-1 is a RAD51i that inhibits RAD51-RAD51 interactions that are important for RAD51-ssDNA nucleoprotein filament formation, the key complex that catalyzes strand exchange during HR [27]. RI-1 has been shown by two groups to radiosensitize glioblastoma cells [28][29]   and it enhances the chemosensitivity of glioblastoma cells to genotoxic damage by alkylating agents [30]. The RAD51i B02 interferes with RAD51-mediated strand invasion [31].  B02 sensitizes glioblastoma cells to alkylating agents [30], and it sensitizes multiple myeloma cells to doxorubicin [32]. Tumors with HR defects, such as BRCA1- and BRCA2-defective breast cancer are sensitive to PARP1i because PARP1 promotes the repair of single-strand lesions that block replication forks and therefore require HR to repair/restart these stressed forks [33][34]. The original B02 compound has been modified into a B02-isomer with greater potency, and the HR defect induced by B02-isomer shows strong synergistic sensitization of tumor cells with PARP1i [35].
PARP1 adds poly(ADP)ribose (PAR) groups to numerous target proteins. PARylation of repair factors is seen in response to DNA damage processed by base excision repair, nucleotide excision repair, single-strand break repair, and DSB repair by canonical non-homologous end-joining (NHEJ), alternative NHEJ, and HR [36]. PARP1i induces replication stress by at least two mechanisms: PARP1i increases the load of unrepaired endogenous DNA lesions (analogous to increased lesion load by exogenous genotoxins), and it blocks replication directly by trapping PARP1 on DNA [37]. In addition, recent studies revealed new roles for PARP1 in chromatin remodeling. DNA repair occurs within the chromatin environment, so it is no surprise that proteins that modify or remodel chromatin influence DNA repair [38][39][40][41][42][43][44][45] and replication stress responses [46][47]. PARP1 has emerged has an important factor in chromatin modeling, and PARylation of both repair factors and chromatin promote the recruitment of repair factors to damaged sites [36][48].
Normal cells cope with PARP1i-induced replication stress by marshaling HR to repair and restart collapsed replication forks, but in cancer cells with HR defects, PARP1i are synthetically lethal [49][50]. First exploited in cancer cells with mutant BRCA1 or BRCA2, PARP1i are potentially valuable against tumors with defects in other HR proteins due to inherited germline mutations or sporadic somatic mutations. The PARP1i olaparib was the first targeted therapeutic approved to treat BRCA-defective ovarian cancer, and PARP1i are being explored to treat BRCA-mutant breast, ovarian, prostate, and pancreatic cancers [51][52][53][54]. In 2020 the FDA approved two PARP1i, olaparib and rucaparib to treat metastatic castration-resistant prostate cancer, and it approved olaparib to treat eligible patients with pancreatic cancer. Because PARP1 plays many roles in DNA repair, replication stress responses, and chromatin remodeling, additional uses for PARP1i in cancer monotherapy, combination therapy, and maintenance therapy continue to be explored [55][56][57][58][59].

5. Exploiting Synthetic Lethality of TKIs Targeting Activated Oncogenes and ATM Inhibitors

When cancer cells activate oncogenes that promote growth, an important consequence is oncogenic stress, also known as oncogenic replicative stress [60]. Oncogenic stress reflects dysregulated replication initiation and progression, including mis-timed origin firing. Many drugs targeting activated oncogenes have been developed and brought to clinical practice, including tyrosine kinase inhibitors (TKIs) that target activated HER2/ERBB2, ALK, KRAS, BRAF, and EGFR [61][62][63][64][65][66]. It was recently shown that blocking oncogenic pathways with targeted TKIs causes moderate stress which results in sublethal DSBs induced by caspase-activated DNase (CAD; also known as DFF40 and DFFB) [67]. When fully activated during apoptosis, CAD is responsible for digesting the genome into ~180 bp “ladders” by cleaving linker DNA between nucleosomes [68]. Although cells survive these TKI/CAD-induced DSBs, their repair depends on ATM, thus ATMi kills cells treated with various TKIs targeting activated oncogenes [67]. This effect appears to be general, as ATMi kills tumor cells treated with cognate TKIs targeting different activated oncogenes (EGFR, ALK, KRAS, and BRAF) in different tumor types (lung, pancreatic, melanoma, and acute myeloid leukemia). Interestingly, TKI + ATMi is cytotoxic even in cells that have gained resistance to the cognate TKI, suggesting ATMi may prove beneficial to patients with TKI-resistant tumors [67]. This TKI + ATMi effect represents a novel approach to exploit replication stress (oncogenic stress) and DDR inhibition to selectively target cancer cells.


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