Abstract
Wnt signaling plays an important role in regulating the biological behavior of cancers, and many drugs targeting this signaling have been developed. Recently, a series of research have revealed that Wnt signaling could regulate DNA damage response (DDR) which is crucial for maintaining the genomic integrity in cells and closely related to cancer genome instability. Many drugs have been developed to target DNA damage response in cancers. Notably, different components of the Wnt and DDR pathways are involved in crosstalk, forming a complex regulatory network and providing new opportunities for cancer therapy. Here, we provide a brief overview of Wnt signaling and DDR in the field of cancer research and review the interactions between these two pathways. Finally, we also discuss the possibility of therapeutic agents targeting Wnt and DDR as potential cancer treatment strategies.
1 Introduction
The Wnt signaling pathway is a complex protein regulatory network cascade, which participates in various biological processes, including embryonic development, tissue development and regeneration, and cancer development and progression. The abnormal activation of Wnt signaling will result in many pathological processes, such as cancer, inflammatory and immune diseases, and metabolic diseases (Clevers and Nusse, 2012; Nusse and Clevers, 2017).
DNA damage response (DDR) is a hierarchical signaling pathway that functions to maintain the genome integrity and stability and is coordinated by a variety of proteins. Numerous studies have demonstrated that DDR deficiency is closely associated with several diseases (Jackson and Bartek, 2009; Ciccia and Elledge, 2010; Lee and Paull, 2021; Stoof et al., 2021; Ye et al., 2021), among which cancer has become a focus of research. DDR has been extensively involved in regulation of cell senescence, carcinogenesis, and cancer progression as well as influencing the efficacy of cancer radiotherapy and chemotherapy. As the majority of anti-tumor therapies primarily target the genomic DNA of cancer cells, enhancement of DDR is closely related to their therapeutic efficacy (Lord and Ashworth, 2012; Su et al., 2023; Traphagen et al., 2023).
Previous studies have reported that Wnt signaling can affect DDR by regulating a variety of factors (Lento et al., 2014; Tao et al., 2015; Liang et al., 2018). In this review, we first introduce the Wnt/β-catenin and DDR signaling pathways and focus on the role of signaling in the regulation of DDR. Wnt/β-catenin pathway and DDR pathway members are potential therapeutic targets for many types of cancer (Lord and Ashworth, 2012; Krishnamurthy and Kurzrock, 2018; Pilié et al., 2019; Wang et al., 2021a). Could this possibly shed new light on clinical decision-making? We describe the molecular mechanisms and associations of the Wnt and DDR pathways with the biological processes involved in cancer and the treatment of cancer and their potential impact on the development of new treatment regimens.
2 Wnt signaling pathway
The Wnt signaling can be activated through the binding of Wnt family member ligand to the membrane receptors like Frizzled (FZD) family receptors, low-density lipoprotein receptor-related protein 5/6 (LRP5/6), and receptor tyrosine kinase-like orphan receptors (ROR1/2). Wnt signaling activation leads to transcriptional activation of multiple downstream effectors (Clevers and Nusse, 2012), and extracellular signals are transmitted through this pathway into the cell via activation of the intracellular segments of receptors on the cell surface, which in turn activates β-catenin-dependent or -independent Wnt signaling cascades. There are several separate Wnt pathways which can engage in crosstalk with one another; these have been summarized as canonical (β-catenin-dependent) and non-canonical signaling (Wnt/Ca2+ (calcium) pathway and Wnt/PCP (planar cell polarity) pathway) pathways (Figure 1). Generally, the canonical Wnt signaling pathway mainly participates in regulating progenitor cell self-renewal, proliferation, or differentiation, while the non-canonical signaling pathway is primarily responsible for the maintenance of cell stemness, cell motility, or antagonism of the canonical pathway (Fodde and Brabletz, 2007; Clevers and Nusse, 2012; Nusse and Clevers, 2017).
FIGURE 1
2.1 The canonical Wnt/β-catenin pathway
The key members of the canonical Wnt signaling pathway include the Wnt family proteins, FZD/LRP6, disheveled protein (Dvl), β-catenin, T lymphocytokine/lymphoenhancer factor (TCF), human lymphoid enhancer factor (LEF), and the β-catenin destruction complex which comprises adenomatous polyposis coli (APC), axin, glycogen synthase kinase-3β (GSK-3β), and casein kinase 1α (CK1α). In the absence of a Wnt signal, β-catenin binds to the destruction complex, resulting in its ubiquitination via proteasomal degradation mediated by β-TrCP. In the presence of Wnt signal, Wnt binds to the FZD and LRP5/6 receptors to activate Dvl protein and inhibit the destruction complex, resulting in the accumulation of free unphosphorylated β-catenin in the cytoplasm, which is then transported to the nucleus where it can combine with TCF/LEF to induce transcription of downstream Wnt signaling genes (Clevers and Nusse, 2012; Nusse and Clevers, 2017).
2.2 The non-canonical Wnt pathway
2.2.1 The Wnt/Ca2+ pathway
The Wnt proteins could bind to the FZD receptors on the cell transmembrane and participate in several cellular processes that are involved in stimulating the isotrimer G protein to further activate PLC. PLC activation could result in elevated release of intracellular Ca2+, reduced cyclic guanosine (cGMP) levels, and activation of Ca2+/calmodulin-dependent protein kinase-II (CaMKII) and PKC; these processes can stimulate NFAT and other transcription factors such as CREB1 (De, 2011).
2.2.2 Wnt/PCP signaling
In Wnt/PCP signaling (Wang et al., 2021a), PCP mainly regulates cell movement direction and cell morphology. Wnt ligands bind to the ROR–FZD receptor complex to recruit and activate Dvl which binds to the small GTPase Rho. Then, the small GTPase Rac1 and Rho together trigger ROCK (Rho kinase) and JNK, thereby contributing to the regulation of cytoskeletal and transcriptional responses.
3 DDR regulators and signaling pathways
Under physiological conditions, DNA damage can be caused by various environmental stimuli and intracellular stress. After suffering DNA damage, cells can have three possible fates: recovering to the normal physiological state, initiation of apoptosis, or survival with damage. Through various regulatory pathways, cells can efficiently recognize DNA damage lesions, activate the DDR, and initiate the corresponding repair mechanism. The DDR involves a series of complex and elaborate regulatory events, including the identification of lesions, activation of checkpoints, remodeling of chromatin, DNA damage repair, cell cycle arrest, and apoptosis.
The DNA repair pathways vary in response to different types of DNA damage, which can be classified as follows: base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR; where another nucleotide chain is required as a repair template), and non-homologous end-joining (NHEJ, where the broken ends are directly connected to the DNA strand). HR and NHEJ are the main repair ways for double-strand breaks (DSBs). HR always occurs in G2 and S phases, during which sister chromatids are present and can provide a template strand, while NHEJ is cell cycle phase-independent. For eukaryotes, NHEJ repairs most DSBs, and HR is preferentially used when the lesion occurs at DNA replication forks.
DDR is majorly regulated by two protein families: the phosphatidylinositol 3-kinase-like protein kinase (PIKK) family (including ATM, ATR, and DNA-PK) and the 16-member poly (ADP) ribose polymerase (PARP) family. Generally speaking, ATM, ATR, DNA-PK, and PARP mainly function as sensors for DNA damage. ATM is recruited by the MRN (MRE11/RAD50/NBS1) complex following recognition of DSBs (Rupnik et al., 2010; Blackford and Jackson, 2017), and ATM is the kinase typically responsible for modulation of cellular responses to DSBs, which comprise DNA repair, checkpoint activation, apoptosis, senescence, and alterations in the chromatin structure (Shiloh and Ziv, 2013; Blackford and Jackson, 2017). ATR is recruited by 9-1-1 (RAD9–RAD1–HUS1) complex to extend tracts of ssDNA (Blackford and Jackson, 2017). ATR is the DNA replication stress response kinase which could phosphorylate numerous substrates under the stimulation of genotoxic stresses. Following detection of DSBs, DNA-PK is recruited by Ku to initiate NHEJ (Graham et al., 2016). Among PARP family proteins, the structure and function of PARP-1 have been well elucidated by researchers. PARP plays a multifaceted role in cellular response to DNA damage. For example, PARP acts as a sensor in DDR that catalyzes the addition of poly (ADP-ribose) chains to histones and other nuclear proteins to recruit DDR factors to chromatin at breakpoints (Amé et al., 2004). PARP could also cause chromatin remodeling and recruit DNA-repair-associated proteins (Haince et al., 2008). In Figure 2, we summarize the DDR processes involving these different sensors, namely, ATM, ATR, DNA-PK, and PARP.
FIGURE 2
The downstream effects of these repair processes involve activation of various substrates to elicit appropriate responses involved in cell fate determination. These downstream effectors include H2AX, CHK1, CHK2, and p53, among others. H2AX is phosphorylated to form γH2AX, which is one of the earliest events in DDR. γH2AX not only generates a signaling cascade to amplify the signal of DDR and recruits the DDR proteins but also regulates chromatin relaxation (Rogakou et al., 1998). CHK1 and CHK2, coordinating DDR by arresting the cell cycle (Abraham, 2001), can phosphorylate p53 at Ser20 (Bode and Dong, 2004). P53 plays an important role in activating repair proteins to promote DNA repair, arresting the cell cycle in G1/S to provide ample time to repair damage, and initiating apoptosis to prevent abnormal genetic information from dividing and growing if the damage proves to be irreparable (Shiloh and Ziv, 2013; Li et al., 2016). Several characteristics of p53 are particularly notable. In the normal physiological state, p53 is presented at low levels in cells because of proteasome-mediated degradation, which is closely related to complex formation with various types of E3 ubiquitin ligases, the most important of which is Mdm2 (Brooks and Gu, 2006). HIPK2, a p53 Ser46 kinase, is retained in an inactive status because of the targeted proteolysis by E3 ubiquitin ligases in unstressed cells, making it an important regulator of stress signaling and DDR (Matt and Hofmann, 2016). When DNA damage is encountered, ATM and ATR kinases could phosphorylate Siah1, resulting in the dissociation of the HIPK2–Siah1 complex and increased stability of the HIPK2 protein (Winter et al., 2008).
4 Wnt and its crosstalk with DDR
Numerous studies have shown that Wnt signaling is highly intertwined with DDR (Zhang et al., 2011; Karimaian et al., 2017; Zhao et al., 2018b). In this section, we elaborate on these specific connections by outlining the roles of key factors (Figure 3).
FIGURE 3
4.1 The role of β-catenin in DDR
β-catenin is implicated in the regulation of DDR (Xu et al., 2008; Zhang et al., 2011; Priolli et al., 2013; Tavana et al., 2013; Chandra et al., 2015; Serebryannyy et al., 2017). Activation of downstream target genes of β-catenin such as cyclin D1 and c-myc proto-oncogenes leads to cell proliferation, differentiation, and maturation (Tulac et al., 2003). Notably, there is a growing list of Wnt/β-catenin target genes which have been found in various species and have been cataloged at: http://www.stanford.edu/group/nusselab/cgi-bin/wnt/target_genes. Based on these data, we have summarized the target genes closely related to DDR and briefly describe their roles in DDR.
4.2 The role of APC in DDR
APC is a key effector of the canonical Wnt signaling pathway involved in downregulating the β-catenin level. Many previous studies have shown that the loss of APC function can cause chromosomal instability (Fodde et al., 2001; Kaplan et al., 2001; Bienz, 2002). Clarke et al. found that APC loss leads to DNA damage and genomic instability in the live cell in a process closely associated with p53 (Méniel et al., 2015). In addition, there have been reports that APC is involved in the BER (Jaiswal and Narayan, 2008; Jaiswal and Narayan, 2011). Moreover, APC loss decreases cancer cell sensitivity to chemotherapy by reducing phosphorylation of ATM/Chk1/Chk2, which in turn influences DDR (Stefanski et al., 2019). APC loss can also increase STAT3 activation, leading to chemotherapy resistance (VanKlompenberg et al., 2017). STAT3 has been shown to take part in DNA repair, as low STAT3 levels can reduce ATM and ATR signaling through MDC1 (Barry et al., 2010).
4.3 Regulation of Axin on DDR
Axin, a key scaffolding protein, is responsible for the formation of the β-catenin destruction complex. Stability of axin protein is regulated by the ubiquitin-proteasome system, and enhancing axin stabilization is a common method of inhibiting Wnt/β-catenin signaling. In DDR, axin interacts with PML to regulate p53-dependent apoptosis in response to DNA damage (Li et al., 2011). Axin is involved in regulating phosphorylation of p53 Ser46 by forming a p53–axin–HIPK2 complex (Rui et al., 2004). Additionally, Lin et al. found that Tip60 interacts with axin in an ATM/ATR/CHK1-dependent way and abrogates Pirh2–axin binding, forming an axin–Tip60–HIPK2–p53 complex and leading to p53 phosphorylation in response to genotoxic stress during radiochemotherapy (Li et al., 2009).
4.4 Regulation of FZD on DDR
FZD is the seven-pass transmembrane receptor of Wnt. FZD5 is a member of the FZD family. Zhao et al. revealed that FZD5 has been involved in triple-negative breast cancer (TNBC) cell G1/S transition and DNA damage repair partially dependent on Wnt7B (Sun et al., 2020). Moreover, FZD5 modulates the downstream effecter FOXM1 in a Wnt/β-catenin-dependent manner to regulate the cell cycle, DNA replication, and DNA damage repair (Sun et al., 2020). In addition, a study on ovarian cancer found that another FZD family member, FZD7, can protect cells from chemotherapy-induced oxidative stress through the FZD7–β-catenin–Tp63–GPX4 pathway (Wang et al., 2021b). Similarly, another study showed that FZD10 can regulate Wnt signaling in BRCA-mutated epithelial ovarian cancers, ultimately contributing to increased HR activity (Fukumoto et al., 2019).
4.5 The effects of GSK-3β on DDR
GSK-3β is involved in multiple intracellular signaling pathways and is a component of the β-catenin destruction complex in Wnt signaling, which determines β-catenin stabilization. In DDR, GSK-3β can phosphorylate several DNA repair factors and affect their interaction with chromatin. For instance, through phosphorylating cyclin D1, CDC25A, and CRY2, GSK-3β can tune DNA repair and cell cycle (Diehl et al., 1998; Harada et al., 2005; Kang et al., 2008). Furthermore, GSK-3β can also phosphorylate B-Myb, leading to the dissociation of B-Myb from the MRN-mediated response to DNA damage (Henrich et al., 2017). Translin-associated protein X (TRAX) is a DNA/RNA-binding protein that participates in various functions, including DNA repair and physical interaction with GSK-3β and other DNA repair factors, to further influence NHEJ-mediated repair (Weng et al., 2018). In the cytoplasm, GSK-3β could phosphorylate targets to trigger proteasomal degradation and promote activation of NF-κB activity to evade apoptosis (Lin et al., 2020). On radiation exposure, GSK-3β translocates from the cytoplasm to the nucleus and phosphorylates 53BP1, an important regulator for DNA repair (Yang et al., 2018). There is strong evidence that GSK-3β plays an important role in DDR; however, whether those functions of GSK-3β depend on Wnt/β-catenin signaling requires further investigation.
4.6 The role of p53 in DDR
In DDR, p53 can be activated in various ways. For example, ATM and ATR can phosphorylate p53 on Ser15 which is thought to inhibit interaction of p53 with the ubiquitin ligase, MDM2, leading to its dissociation from MDM2, thereby contributing to p53 stabilization (Shiloh and Ziv, 2013). Likewise, the p53 co-factor, hnRNPK, can be phosphorylated by ATM and protect p53 from MDM2-mediated degradation (Moumen et al., 2013). In the Wnt pathway, Wnt/β-catenin can promote the expression of ARF, which binds to MDM2 leading to its inactivation (Kubbutat et al., 1997). In contrast, the activation of p53 could trigger the Siah/SIP/Skp1/Ebi pathway for β-catenin ubiquitination degradation and then reduce activity of TCF/LEF (Matsuzawa and Reed, 2001). Accordingly, p53 is a key factor in the crosstalk between the Wnt/β-catenin signaling pathway and DDR.
4.7 Regulation of PARP on DDR
In general, PARP, a DNA damage sensor, is activated by recognizing damaged DNA fragments. DNA damage would induce auto-polyADP-ribosylation of the PARP-1 protein to inhibit the functional interaction of PARP-1 with TCF-4 and participate in the transcriptional regulation of TCF-4/β-catenin complex target genes, such as cyclin D1 and c-myc (Idogawa et al., 2005). In addition, Ku70 is an inhibitor of the β-catenin/TCF-4 transcriptional complex, and PARP-1 could compete with Ku70 for binding to TCF-4, thereby modifying transcriptional activity of TCF-4 (Idogawa et al., 2007). Moreover, there is considerable evidence that Wnt/β-catenin signaling activation can promote resistance to PARP inhibitors (Fukumoto et al., 2019; Yamamoto et al., 2019; Zhu et al., 2021). Therefore, PARP may provide a novel linkage between Wnt/β-catenin signaling and DDR.
In summary, there are many connections between Wnt and DDR (Table 1); however, whether these factors regulate DDR directly via Wnt signaling or independent of the Wnt signaling pathway warrants further investigation.
TABLE 1
| Gene | Function in DDR |
|---|---|
| c-myc | Regulates the cell cycle, telomere homeostasis, and c-myc target genes are involved in DDR, DNA synthesis, and apoptosis |
| n-myc | Regulates DDR |
| Cyclin D1 | Regulates cell cycle and DNA repair |
| uPAR | Activates DNA repair signaling pathway |
| MMP-7 | DNA repair |
| Endothelin-1 | Enhances DNA repair |
| Jagged1 | DNA repair |
| iNOS | Product NO causes DNA damage and inhibits DNA repair proteins |
| Telomerase | Sustains DNA damage signals in senescent cells, regulates apoptosis, and protects the cell against DNA damage |
| Sox9 | Increases cell survival and regulates the cell cycle |
| Sox17 | Downregulation of DDR genes |
| Runx2 | Regulates the cell cycle, DNA repair, and apoptosis |
| SALL4 | Activates the critical ATM-dependent cellular responses and chromatin remodeling |
| Osteoprotegerin | Reduces UV-induced apoptosis |
| CCN1 (Cyr61) | Regulates the cell cycle |
| Sox2 | Regulates the cell cycle |
| PTTG (securin) | Regulates cell cycle, activates DDR, and modulates DDR gene expression |
| Nanog | Deregulates DDR and chromatin remodeling |
| OCT-4 | Regulates the homologous recombination, regulates the cell cycle, and modulation of p53 |
| Fibronectin | Regulates the cell cycle and priming and potentiation of DDR |
| Wnt3a | Regulates the cell cycle |
| Connexin43 | Regulates the cell cycle |
| RARγ | Involved in DNA damage-induced necroptosis and extrinsic apoptosis |
| MITF | DNA repair, activates DDR signaling cascade, and regulates the cell cycle |
| Stra6 | Apoptosis |
| Autotaxin | Involved in DDR and DNA repair |
| WISP | Apoptosis |
| COX-2 | Prevents DNA damage |
| Nkx2.2 | Regulates ATM activity |
| WISP-1 | Regulates p53-mediated apoptosis |
| Periostin | Periostin-deficient embryos could be linked to improve DNA damage repair and regulates the cell cycle |
| β-TrCP | Regulates the cell cycle and DNA repair |
| CDC25A | Regulates the cell cycle |
| P16 | Regulates the cell cycle and induces DDR |
Function of Wnt target genes in DDR.
5 Potential treatment strategies
At present, initiation and increase of DNA damage in cancer cell is a commonly exploited strategy for treating cancer and plays an effective therapeutic role; however, some cancer cells can develop resistance to DNA damage drugs by activating DDR. Increased DNA repair leads to resistance of cancer cells to targeted local (radiotherapy) or systemic (chemotherapy) treatments. Numerous kinds of drugs used for cancer chemotherapy, such as Adriamycin, etoposide, bleomycin, and cisplatin, are characterized as intense inducers of DNA damage and could effectively activate the intracellular DDR (Jackson and Bartek, 2009). All parts of DDR require proper coordination to maintain genome stability, and they can all influence the effects of cancer treatment. Therefore, DDR components can serve as radiation and chemical sensitization targets in cancer treatment. Knowledge of the DDR defects that are present in cancer can also allow for the selection of optimal treatments that can efficiently kill the cancer cells (Goldstein and Kastan, 2015). Currently, many drugs targeting the DDR have been developed to treat tumors, which are shown in Schedule 1. A summary of clinical trials on Wnt/β-catenin-targeted agents is presented in Table 2.
TABLE 2
| Target | Mechanism of action | Compound name | Cancer type | Trial identifier | Reference |
|---|---|---|---|---|---|
| PORCN | Porcupine inhibitor | LGK974 (Wnt974) | Pancreatic cancer, BRAF mutant colorectal cancer, melanoma, triple-negative breast cancer, head and neck squamous cell cancer, cervical squamous cell cancer, esophageal squamous cell cancer, and lung squamous cell cancer | NCT01351103 | Rodon et al. (2021) |
| Metastatic colorectal cancer | NCT02278133 | Tabernero et al. (2023) | |||
| ETC-159 (ETC-1922159) | Solid tumors | NCT02521844 | Katoh (2018) | ||
| RXC004 | Colorectal cancer | NCT04907539 | |||
| Advanced solid tumors | NCT04907851 | Phillips et al. (2022) | |||
| Cancer and solid tumors | NCT03447470 | ||||
| CGX1321 | Colorectal adenocarcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma, bile duct carcinoma, hepatocellular carcinoma, esophageal carcinoma, and gastrointestinal cancer | NCT03507998 | Li et al., 2019; Goldsberry et al., 2020; Shah et al., 2021 | ||
| Wnt | Preventing Wnt binding to FZD | Ipafricept (OMP-54F28) | Hepatocellular cancer and liver cancer | NCT02069145 | Jimeno et al., 2017 |
| Ovarian cancer | NCT02092363 | Moore et al. (2019) | |||
| Pancreatic cancer and stage IV pancreatic cancer | NCT02050178 | ||||
| Solid tumors | NCT01608867 | ||||
| Wnt5a agonist | Foxy-5 | Metastatic breast cancer, colorectal cancer, and prostate cancer | NCT02020291 and NCT02655952 | Säfholm et al., 2008; Canesin et al., 2017; Osman et al., 2019 | |
| Colon cancer | NCT03883802 | ||||
| FZD | Inhibits Wnt signaling by binding FZD 1, 2, 5, 7, 8 | Vantictumab (OMP-18R5) | Solid tumors | NCT01345201 and NCT01957007 | |
| Pancreatic cancer and stage IV pancreatic cancer | NCT02005315 | Davis et al., 2020; Diamond et al., 2020 | |||
| Metastatic breast cancer | NCT01973309 | ||||
| FZD10 antagonist | OTSA101-DTPA-90Y | Synovial sarcoma | NCT01469975 | Goswami and Patel (2021) | |
| FZD8 decoy receptor | Ipafricept (OMP-54F28) | Solid tumors | NCT01608867 | ||
| Hepatocellular cancer and liver cancer | NCT02069145 | Jimeno et al., 2017; Moore et al., 2019; Dotan et al., 2020 | |||
| Ovarian cancer | NCT02092363 | ||||
| Pancreatic cancer | NCT02050178 | ||||
| ROR1 | Anti-ROR1 antibody | Cirmtuzumab (UC-961) | Chronic lymphocytic leukemia | NCT02860676 | |
| NCT02222688 and NCT03088878 | |||||
| Metastatic castration-resistant prostate cancer | NCT05156905 | Choi et al., 2015; Choi et al., 2018 | |||
| Chronic lymphocytic leukemia | NCT04501939, NCT02860676, and NCT02222688 | ||||
| Breast neoplasms | NCT02776917 | ||||
| B-cell chronic lymphocytic leukemia, small lymphocytic lymphoma, and mantle cell lymphoma | NCT03088878 | ||||
| NBE-002 | Advanced solid tumor, advanced cancer, and triple-negative breast cancer | NCT04441099 | |||
| Overexpressing ROR1 | Zilovertamab vedotin (VLS-101 and MK-2140) | Hematologic malignancies | NCT03833180 | ||
| Solid tumors | NCT04504916 | Kipps, 2021; Vaisitti et al., 2021 | |||
| Relapsed or refractory diffuse large B-cell lymphoma | NCT05139017 | ||||
| NVG-111 (RP2D) | Chronic lymphocytic leukemia and mantle cell lymphoma | NCT04763083 | |||
| Targeting of genetically engineered autologous T-lymphocytes to ROR1+ tumors | Anti-ROR1 CAR | ROR1+ tumors | NCT02706392 | ||
| ROR2 | Targeting of genetically engineered autologous T-lymphocytes to ROR2+ tumors | CCT301CAR (CCT301-38 and CCT301-59) | Renal cell carcinoma | NCT03393936 | |
| Solid tumor, soft tissue sarcoma, gastric cancer, pancreatic cancer, and bladder cancer | NCT03960060 | ||||
| Conditionally active biologic anti-ROR2 antibody drug conjugate | Ozuriftamab vedotin (CAB-ROR2-ADC and BA3021) | Non-small cell lung cancer, triple-negative breast cancer, melanoma, and head and neck cancer | NCT03504488 | ||
| Recurrent or metastatic squamous cell cancer of the head and neck | NCT05271604 | ||||
| Ovarian cancer | NCT04918186 | ||||
| Non-small cell lung cancer | NCT04681131 | ||||
| CBP | CBP/β-catenin antagonist | PRI-724 | Colorectal cancer | NCT02413853 and NCT04351009 | |
| Advanced or metastatic pancreatic cancer | NCT01764477 | ||||
| Advanced myeloid malignancies | NCT01606579 | ||||
| Advanced solid tumors | NCT01302405 | ||||
| β-catenin | Degrading β-catenin | CWP232291 | Acute myeloid leukemia and chronic myelomonocytic leukemia | NCT01398462 | Pak et al., 2019; Lee et al., 2020; Wang et al., 2022 |
| Acute myeloid leukemia | NCT03055286 | ||||
| Multiple myeloma | NCT02426723 |
Drug target and clinical trials on Wnt/β-catenin-targeted agents in cancer.
Theoretically, targeting both DDR and Wnt signaling could serve as potential treatment strategies for cancer. Another common denominator of them is that DDR and Wnt signaling have been associated with therapeutic resistance (Martin-Orozco et al., 2019). Alterations in Wnt signaling are also closely associated with maintenance of cancer stem cell (CSCs) proliferation, as hyperactivation of the Wnt signaling pathway is critical in supporting cancer cell survival in the context of treatment with anti-cancer drugs and ultimately leads to cancer progression. Therefore, the design and development of appropriate anti-cancer strategies based on Wnt targets may have important therapeutic value in treating cancer cells, thereby enhancing the therapeutic efficacy of these strategies (Mukherjee and Panda, 2020; Zhang and Wang, 2020). The formation of drug resistance could be attributed to some different mechanisms such as the acquisition of quiescence, the interaction with the microenvironment, drug efflux capacity, increased resistance to apoptosis, and increased DNA repair. For example, FZD5 enhances DNA damage repair and chemoresistance (Sun et al., 2020). GSK-3β promotes resistance of cancer cells to DNA damage chemotherapeutic agents and radiation through regulating DNA repair and stemness of cancer cells (Lin et al., 2020). YAP/TAZ is a Wnt regulator that can be activated to protect cancer cells from DNA damage (de Lau et al., 2014). Furthermore, the role of Wnt signaling in promoting DNA damage repair and inhibiting apoptosis contributes to cancer resistance to radiation (Jun et al., 2016; Zhao et al., 2018a).
Most current anti-cancer chemotherapy approaches function by killing highly proliferating cells, which in many cancers are mostly non-CSCs. However, small CSC populations present in cancer have a higher repair mechanism and are also highly resistant to chemotherapy. In addition, radiotherapy and chemotherapy may trigger a series of cellular stress response mechanisms that enhance stem cell properties of non-CSCs, thereby improving their adaptation and survival. Therefore, compared with previous therapies, new combination therapies, which can kill both CSCs and non-CSCs while preventing the transition from non-CSCs to CSCs, require consideration. It would be possible to develop a therapeutic strategy which combines DDR-targeting drugs with Wnt-targeting drugs to increase sensitivity of cytotoxic drugs while contributing anti-CSC effects. Importantly, the connection points between the DDR and Wnt warrant further investigation, as drugs targeting these points are likely to inhibit both DDR and CSCs simultaneously.
6 Discussion and conclusion
In the context of cancer, increased Wnt signaling is beneficial and reflected in enhancement of DDR, endowing cancer cells with increased ability to repair themselves during radiation or chemotherapy. The association between Wnt signaling and DDR in the post-carcinogenesis stage have been well studied, but the relationship between these two pathways during the process of carcinogenesis requires further investigation. There is a strong correlation between carcinogenesis and inadequate repair of DNA damage; however, whether Wnt signaling is involved in this process remains unknown. Future studies are required to investigate whether Wnt signaling can influence carcinogenesis via regulation of DDR.
Although Wnt signaling and the DDR are closely related, the effects generated by different specific points of crosstalk are unknown. Identification of an appropriate regulator as a therapeutic target may be beneficial to cancer treatment. Compared with single-drug chemotherapy or radiotherapy, drug combination may achieve double efficacy with half the input. From another perspective, a triple therapy including DDR-targeting drugs and Wnt-targeting drugs has the potential to enhance the efficacy of radiotherapy and chemotherapy. Although our theory may be considered oversimplified, identification of crosstalk between the Wnt signaling pathway and DNA damage recognition has potential to provide novel insights into cancer therapy.
Statements
Author contributions
XZ and XY: conceptualization. XZ: data curation and writing–original draft preparation. XY: visualization and investigation. XZ and XY: supervision. XZ and XY: writing–reviewing and editing. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by the 345 Talent Project of Shengjing Hospital of China Medical University.
Acknowledgments
The authors thank the Department of Otolaryngology, Head, and Neck Surgery, Shengjing Hospital of China Medical University. This work was supported by the 345 Talent Project of Shengjing Hospital of China Medical University. The authors also thank biorender.com for creating Figure 3.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
1
AbrahamR. T. (2001). Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes & Dev.15 (17), 2177–2196. 10.1101/gad.914401
2
AméJ.-C.SpenlehauerC.de MurciaG. (2004). The PARP superfamily. BioEssays news Rev. Mol. Cell. Dev. Biol.26 (8), 882–893. 10.1002/bies.20085
3
BarryS. P.TownsendP. A.KnightR. A.ScarabelliT. M.LatchmanD. S.StephanouA. (2010). STAT3 modulates the DNA damage response pathway. Int. J. Exp. Pathology91 (6), 506–514. 10.1111/j.1365-2613.2010.00734.x
4
BienzM. (2002). The subcellular destinations of APC proteins. Nat. Rev. Mol. Cell Biol.3 (5), 328–338. 10.1038/nrm806
5
BlackfordA. N.JacksonS. P. (2017). ATM, ATR, and DNA-PK: The trinity at the heart of the DNA damage response. Mol. Cell66 (6), 801–817. 10.1016/j.molcel.2017.05.015
6
BodeA. M.DongZ. (2004). Post-translational modification of p53 in tumorigenesis. Nat. Rev. Cancer4 (10), 793–805. 10.1038/nrc1455
7
BrooksC. L.GuW. (2006). p53 ubiquitination: Mdm2 and beyond. Mol. Cell21 (3), 307–315. 10.1016/j.molcel.2006.01.020
8
CanesinG.Evans-AxelssonS.HellstenR.KrzyzanowskaA.PrasadC. P.BjartellA.et al (2017). Treatment with the WNT5A-mimicking peptide Foxy-5 effectively reduces the metastatic spread of WNT5A-low prostate cancer cells in an orthotopic mouse model. PLoS One12 (9), e0184418. 10.1371/journal.pone.0184418
9
ChandraA.LinT.ZhuJ.TongW.HuoY.JiaH.et al (2015). PTH1-34 blocks radiation-induced osteoblast apoptosis by enhancing DNA repair through canonical Wnt pathway. J. Biol. Chem.290 (1), 157–167. 10.1074/jbc.M114.608158
10
ChoiM. Y.WidhopfG. F.2ndGhiaE. M.KidwellR. L.HasanM. K.YuJ.et al (2018). Phase I trial: Cirmtuzumab inhibits ROR1 signaling and stemness signatures in patients with chronic lymphocytic leukemia. Cell Stem Cell22 (6), 951–959.e3. 10.1016/j.stem.2018.05.018
11
ChoiM. Y.WidhopfG. F.2ndWuC. C.CuiB.LaoF.SadaranganiA.et al (2015). Pre-clinical specificity and safety of UC-961, a first-in-class monoclonal antibody targeting ROR1. Clin. Lymphoma Myeloma Leuk.15, S167–S169. 10.1016/j.clml.2015.02.010
12
CicciaA.ElledgeS. J. (2010). The DNA damage response: Making it safe to play with knives. Mol. Cell40 (2), 179–204. 10.1016/j.molcel.2010.09.019
13
CleversH.NusseR. (2012). Wnt/β-catenin signaling and disease. Cell149 (6), 1192–1205. 10.1016/j.cell.2012.05.012
14
DavisS. L.CardinD. B.ShahdaS.LenzH. J.DotanE.O'NeilB. H.et al (2020). A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer. Invest. New Drugs38 (3), 821–830. 10.1007/s10637-019-00824-1
15
DeA. (2011). Wnt/Ca2+ signaling pathway: A brief overview. Acta biochimica biophysica Sinica43 (10), 745–756. 10.1093/abbs/gmr079
16
de LauW.PengW. C.GrosP.CleversH. (2014). The R-spondin/lgr5/rnf43 module: Regulator of Wnt signal strength. Genes & Dev.28 (4), 305–316. 10.1101/gad.235473.113
17
DiamondJ. R.BecerraC.RichardsD.MitaA.OsborneC.O'ShaughnessyJ.et al (2020). Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer. Breast Cancer Res. Treat.184 (1), 53–62. 10.1007/s10549-020-05817-w
18
DiehlJ. A.ChengM.RousselM. F.SherrC. J. (1998). Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes & Dev.12 (22), 3499–3511. 10.1101/gad.12.22.3499
19
DotanE.CardinD. B.LenzH. J.MessersmithW.O'NeilB.CohenS. J.et al (2020). Phase ib study of Wnt inhibitor ipafricept with gemcitabine and nab-paclitaxel in patients with previously untreated stage IV pancreatic cancer. Clin. Cancer Res.26 (20), 5348–5357. 10.1158/1078-0432.Ccr-20-0489
20
FoddeR.BrabletzT. J. C. (2007). Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Wnt/β-catenin Signal. cancer stemness malignant Behav.19 (2), 150–158. 10.1016/j.ceb.2007.02.007
21
FoddeR.KuipersJ.RosenbergC.SmitsR.KielmanM.GasparC.et al (2001). Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat. Cell Biol.3 (4), 433–438. 10.1038/35070129
22
FukumotoT.ZhuH.NacarelliT.KarakashevS.FatkhutdinovN.WuS.et al (2019). N6-Methylation of adenosine of FZD10 mRNA contributes to PARP inhibitor resistance. Cancer Res.79 (11), 2812–2820. 10.1158/0008-5472.CAN-18-3592
23
GoldsberryW. N.Meza-PerezS.LondoñoA. I.KatreA. A.MottB. T.RoaneB. M.et al (2020). Inhibiting WNT ligand production for improved immune recognition in the ovarian tumor microenvironment. Cancers (Basel)12 (3), 766. 10.3390/cancers12030766
24
GoldsteinM.KastanM. B. (2015). The DNA damage response: Implications for tumor responses to radiation and chemotherapy. Annu. Rev. Med.66, 129–143. 10.1146/annurev-med-081313-121208
25
GoswamiV. G.PatelB. D. (2021). Recent updates on Wnt signaling modulators: A patent review (2014-2020). Expert Opin. Ther. Pat.31 (11), 1009–1043. 10.1080/13543776.2021.1940138
26
GrahamT. G. W.WalterJ. C.LoparoJ. J. (2016). Two-stage synapsis of DNA ends during non-homologous end joining. Mol. Cell61 (6), 850–858. 10.1016/j.molcel.2016.02.010
27
HainceJ.-F.McDonaldD.RodrigueA.DéryU.MassonJ.-Y.HendzelM. J.et al (2008). PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. J. Biol. Chem.283 (2), 1197–1208. 10.1074/jbc.M706734200
28
HaradaY.SakaiM.KurabayashiN.HirotaT.FukadaY. (2005). Ser-557-phosphorylated mCRY2 is degraded upon synergistic phosphorylation by glycogen synthase kinase-3 beta. J. Biol. Chem.280 (36), 31714–31721. 10.1074/jbc.M506225200
29
HenrichS. M.UsadelC.WerweinE.BurdovaK.JanscakP.FerrariS.et al (2017). Interplay with the Mre11-Rad50-Nbs1 complex and phosphorylation by GSK3β implicate human B-Myb in DNA-damage signaling. Sci. Rep.7, 41663. 10.1038/srep41663
30
IdogawaM.MasutaniM.ShitashigeM.HondaK.TokinoT.ShinomuraY.et al (2007). Ku70 and poly(ADP-ribose) polymerase-1 competitively regulate beta-catenin and T-cell factor-4-mediated gene transactivation: Possible linkage of DNA damage recognition and Wnt signaling. Cancer Res.67 (3), 911–918. 10.1158/0008-5472.CAN-06-2360
31
IdogawaM.YamadaT.HondaK.SatoS.ImaiK.HirohashiS. (2005). Poly(ADP-ribose) polymerase-1 is a component of the oncogenic T-cell factor-4/beta-catenin complex. Gastroenterology128 (7), 1919–1936. 10.1053/j.gastro.2005.03.007
32
JacksonS. P.BartekJ. (2009). The DNA-damage response in human biology and disease. Nature461 (7267), 1071–1078. 10.1038/nature08467
33
JaiswalA. S.NarayanS. (2008). A novel function of adenomatous polyposis coli (APC) in regulating DNA repair. Cancer Lett.271 (2), 272–280. 10.1016/j.canlet.2008.06.024
34
JaiswalA. S.NarayanS. (2011). Assembly of the base excision repair complex on abasic DNA and role of adenomatous polyposis coli on its functional activity. Biochemistry50 (11), 1901–1909. 10.1021/bi102000q
35
JimenoA.GordonM.ChughR.MessersmithW.MendelsonD.DupontJ.et al (2017). A first-in-human phase I study of the anticancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors. Clin. Cancer Res.23 (24), 7490–7497. 10.1158/1078-0432.Ccr-17-2157
36
JunS.JungY.-S.SuhH. N.WangW.KimM. J.OhY. S.et al (2016). LIG4 mediates Wnt signalling-induced radioresistance. Nat. Commun.7, 10994. 10.1038/ncomms10994
37
KangT.WeiY.HonakerY.YamaguchiH.AppellaE.HungM.-C.et al (2008). GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers. Cancer Cell13 (1), 36–47. 10.1016/j.ccr.2007.12.002
38
KaplanK. B.BurdsA. A.SwedlowJ. R.BekirS. S.SorgerP. K.NäthkeI. S. (2001). A role for the Adenomatous Polyposis Coli protein in chromosome segregation. Nat. Cell Biol.3 (4), 429–432. 10.1038/35070123
39
KarimaianA.MajidiniaM.BaghiH. B.YousefiB. J. D. (2017). The crosstalk between Wnt/β-catenin signaling pathway with DNA damage response and oxidative stress: Implications in cancer therapy. DNA Repair51, 14–19. 10.1016/j.dnarep.2017.01.003
40
KatohM. (2018). Multi-layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β-catenin signaling activation (Review). Int. J. Mol. Med.42 (2), 713–725. 10.3892/ijmm.2018.3689
41
KippsT. J. (2021). Mining the microenvironment for therapeutic targets in chronic lymphocytic leukemia. Cancer J.27 (4), 306–313. 10.1097/ppo.0000000000000536
42
KrishnamurthyN.KurzrockR. (2018). Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treat. Rev.62, 50–60. 10.1016/j.ctrv.2017.11.002
43
KubbutatM. H.JonesS. N.VousdenK. H. (1997). Regulation of p53 stability by Mdm2. Nature387 (6630), 299–303. 10.1038/387299a0
44
LeeJ. H.FaderlS.PagelJ. M.JungC. W.YoonS. S.PardananiA. D.et al (2020). Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome. Blood Adv.4 (9), 2032–2043. 10.1182/bloodadvances.2019000757
45
LeeJ. H.PaullT. T. (2021). Cellular functions of the protein kinase ATM and their relevance to human disease. Nat. Rev. Mol. Cell Biol.22 (12), 796–814. 10.1038/s41580-021-00394-2
46
LentoW.ItoT.ZhaoC.HarrisJ. R.HuangW.JiangC.et al (2014). Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration. Genes & Dev.28 (9), 995–1004. 10.1101/gad.231944.113
47
LiC.LiangY.CaoJ.ZhangN.WeiX.TuM.et al (2019). The delivery of a Wnt pathway inhibitor toward CSCs requires stable liposome encapsulation and delayed drug release in tumor tissues. Mol. Ther.27 (9), 1558–1567. 10.1016/j.ymthe.2019.06.013
48
LiQ.HeY.WeiL.WuX.WuD.LinS.et al (2011). AXIN is an essential co-activator for the promyelocytic leukemia protein in p53 activation. Oncogene30 (10), 1194–1204. 10.1038/onc.2010.499
49
LiQ.LinS.WangX.LianG.LuZ.GuoH.et al (2009). Axin determines cell fate by controlling the p53 activation threshold after DNA damage. Nat. Cell Biol.11 (9), 1128–1134. 10.1038/ncb1927
50
LiT.LiuX.JiangL.ManfrediJ.ZhaS.GuW. (2016). Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging. Oncotarget7 (11), 11838–11849. 10.18632/oncotarget.7864
51
LiangY.FengY.ZongM.WeiX.-F.LeeJ.FengY.et al (2018). β-catenin deficiency in hepatocytes aggravates hepatocarcinogenesis driven by oncogenic β-catenin and MET. Hepatol. Baltim. Md67 (5), 1807–1822. 10.1002/hep.29661
52
LinJ.SongT.LiC.MaoW. (2020). GSK-3β in DNA repair, apoptosis, and resistance of chemotherapy, radiotherapy of cancer. Biochimica biophysica acta. Mol. Cell Res.1867 (5), 118659. 10.1016/j.bbamcr.2020.118659
53
LordC. J.AshworthA. (2012). The DNA damage response and cancer therapy. Nature481 (7381), 287–294. 10.1038/nature10760
54
Martin-OrozcoE.Sanchez-FernandezA.Ortiz-ParraI.Ayala-San NicolasM. (2019). WNT signaling in tumors: The way to evade drugs and immunity. Front. Immunol.10, 2854. 10.3389/fimmu.2019.02854
55
MatsuzawaS. I.ReedJ. C. (2001). Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. Mol. Cell7 (5), 915–926. 10.1016/s1097-2765(01)00242-8
56
MattS.HofmannT. G. (2016). The DNA damage-induced cell death response: A roadmap to kill cancer cells. Cell. Mol. life Sci. CMLS73 (15), 2829–2850. 10.1007/s00018-016-2130-4
57
MénielV.MeggesM.YoungM. A.ColeA.SansomO. J.ClarkeA. R. (2015). Apc and p53 interaction in DNA damage and genomic instability in hepatocytes. Oncogene34 (31), 4118–4129. 10.1038/onc.2014.342
58
MooreK. N.GundersonC. C.SabbatiniP.McMeekinD. S.Mantia-SmaldoneG.BurgerR. A.et al (2019). A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer. Gynecol. Oncol.154 (2), 294–301. 10.1016/j.ygyno.2019.04.001
59
MoumenA.MagillC.DryK. L.JacksonS. P. (2013). ATM-dependent phosphorylation of heterogeneous nuclear ribonucleoprotein K promotes p53 transcriptional activation in response to DNA damage. Cell cycleGeorget. Tex.)12 (4), 698–704. 10.4161/cc.23592
60
MukherjeeN.PandaC. K. (2020). Wnt/β-Catenin signaling pathway as chemotherapeutic target in breast cancer: An update on pros and cons. Clin. Breast Cancer20 (5), 361–370. 10.1016/j.clbc.2020.04.004
61
NusseR.CleversH. (2017). Wnt/β-Catenin signaling, disease, and emerging therapeutic modalities. Cell169 (6), 985–999. 10.1016/j.cell.2017.05.016
62
OsmanJ.BellamkondaK.LiuQ.AnderssonT.SjölanderA. (2019). The WNT5A agonist Foxy5 reduces the number of colonic cancer stem cells in a xenograft mouse model of human colonic cancer. Anticancer Res.39 (4), 1719–1728. 10.21873/anticanres.13278
63
PakS.ParkS.KimY.ParkJ. H.ParkC. H.LeeK. J.et al (2019). The small molecule WNT/β-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway. J. Exp. Clin. Cancer Res.38 (1), 342. 10.1186/s13046-019-1342-5
64
PhillipsC.BhamraI.EagleC.FlanaganE.ArmerR.JonesC. D.et al (2022). The Wnt pathway inhibitor RXC004 blocks tumor growth and reverses immune evasion in Wnt ligand-dependent cancer models. Cancer Res. Commun.2 (9), 914–928. 10.1158/2767-9764.Crc-21-0095
65
PiliéP. G.TangC.MillsG. B.YapT. A. (2019). State-of-the-art strategies for targeting the DNA damage response in cancer. Nat. Rev. Clin. Oncol.16 (2), 81–104. 10.1038/s41571-018-0114-z
66
PriolliD. G.CanelloiT. P.LopesC. O.ValdíviaJ. C. M.MartinezN. P.AçariD. P.et al (2013). Oxidative DNA damage and β-catenin expression in colorectal cancer evolution. Int. J. colorectal Dis.28 (5), 713–722. 10.1007/s00384-013-1688-7
67
RodonJ.ArgilésG.ConnollyR. M.VaishampayanU.de JongeM.GarraldaE.et al (2021). Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours. Br. J. Cancer125 (1), 28–37. 10.1038/s41416-021-01389-8
68
RogakouE. P.PilchD. R.OrrA. H.IvanovaV. S.BonnerW. M. (1998). DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem.273 (10), 5858–5868. 10.1074/jbc.273.10.5858
69
RuiY.XuZ.LinS.LiQ.RuiH.LuoW.et al (2004). Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation. EMBO J.23 (23), 4583–4594. 10.1038/sj.emboj.7600475
70
RupnikA.LowndesN. F.GrenonM. (2010). MRN and the race to the break. Chromosoma119 (2), 115–135. 10.1007/s00412-009-0242-4
71
SäfholmA.TuomelaJ.RosenkvistJ.DejmekJ.HärkönenP.AnderssonT. (2008). The Wnt-5a-derived hexapeptide Foxy-5 inhibits breast cancer metastasis in vivo by targeting cell motility. Clin. Cancer Res.14 (20), 6556–6563. 10.1158/1078-0432.Ccr-08-0711
72
SerebryannyyL. A.YemelyanovA.GottardiC. J.de LanerolleP. (2017). Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin. J. Cell Sci.130 (10), 1717–1729. 10.1242/jcs.199893
73
ShahK.PanchalS.PatelB. (2021). Porcupine inhibitors: Novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway. Pharmacol. Res.167, 105532. 10.1016/j.phrs.2021.105532
74
ShilohY.ZivY. (2013). The ATM protein kinase: Regulating the cellular response to genotoxic stress, and more. Nat. Rev. Mol. Cell Biol.14 (4), 197–210. 10.1038/nrm3546
75
StefanskiC. D.KefflerK.McClintockS.MilacL.ProsperiJ. R. (2019). APC loss affects DNA damage repair causing doxorubicin resistance in breast cancer cells. Neoplasia (New York, N.Y.)21 (12), 1143–1150. 10.1016/j.neo.2019.09.002
76
StoofJ.HarroldE.MariottinoS.LoweryM. A.WalshN. (2021). DNA damage repair deficiency in pancreatic ductal adenocarcinoma: Preclinical models and clinical perspectives. Front. Cell Dev. Biol.9, 749490. 10.3389/fcell.2021.749490
77
SuY. L.XiaoL. Y.HuangS. Y.WuC. C.ChangL. C.ChenY. H.et al (2023). Inhibiting WEE1 augments the antitumor efficacy of Cisplatin in urothelial carcinoma by enhancing the DNA damage process. Cells12 (11), 1471. 10.3390/cells12111471
78
SunY.WangZ.NaL.DongD.WangW.ZhaoC. (2020). FZD5 contributes to TNBC proliferation, DNA damage repair and stemness. Cell Death Dis.11 (12), 1060. 10.1038/s41419-020-03282-3
79
TaberneroJ.Van CutsemE.GarraldaE.TaiD.De BraudF.GevaR.et al (2023). A phase ib/II study of WNT974 + encorafenib + cetuximab in patients with BRAF V600e-mutant KRAS wild-type metastatic colorectal cancer. Oncologist28 (3), 230–238. 10.1093/oncolo/oyad007
80
TaoS.TangD.MoritaY.SperkaT.OmraniO.LechelA.et al (2015). Wnt activity and basal niche position sensitize intestinal stem and progenitor cells to DNA damage. EMBO J.34 (5), 624–640. 10.15252/embj.201490700
81
TavanaO.Puebla-OsorioN.KimJ.SangM.JangS.ZhuC. (2013). Ku70 functions in addition to nonhomologous end joining in pancreatic β-cells: A connection to β-catenin regulation. Diabetes62 (7), 2429–2438. 10.2337/db12-1218
82
TraphagenN. A.SchwartzG. N.TauS.RobertsA. M.JiangA.HosfordS. R.et al (2023). Estrogen therapy induces receptor-dependent DNA damage enhanced by PARP inhibition in ER+ breast cancer. Clin. Cancer Res.23, 488. 10.1158/1078-0432.Ccr-23-0488
83
TulacS.NayakN. R.KaoL. C.Van WaesM.HuangJ.LoboS.et al (2003). Identification, characterization, and regulation of the canonical Wnt signaling pathway in human endometrium. J. Clin. Endocrinol. metabolism88 (8), 3860–3866. 10.1210/jc.2003-030494
84
VaisittiT.ArrugaF.VitaleN.LeeT. T.KoM.ChadburnA.et al (2021). ROR1 targeting with the antibody-drug conjugate VLS-101 is effective in Richter syndrome patient-derived xenograft mouse models. Blood137 (24), 3365–3377. 10.1182/blood.2020008404
85
VanKlompenbergM. K.LeydenE.ArnasonA. H.ZhangJ.-T.StefanskiC. D.ProsperiJ. R. (2017). APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation. Oncotarget8 (61), 102868–102879. 10.18632/oncotarget.22263
86
WangJ.FengD.GaoB. (2021a). An overview of potential therapeutic agents targeting WNT/PCP signaling. Handb. Exp. Pharmacol.269, 175–213. 10.1007/164_2021_533
87
WangJ.ZhaoG.CondelloS.HuangH.CardenasH.TannerE. J.et al (2021b). Frizzled-7 identifies platinum-tolerant ovarian cancer cells susceptible to ferroptosis. Cancer Res.81 (2), 384–399. 10.1158/0008-5472.CAN-20-1488
88
WangW.ChoU.YooA.JungC. L.KimB.KimH.et al (2022). Wnt/β-Catenin inhibition by CWP232291 as a novel therapeutic strategy in ovarian cancer. Front. Oncol.12, 852260. 10.3389/fonc.2022.852260
89
WengY.-T.ChienT.KuanI. I.ChernY. (2018). The TRAX, DISC1, and GSK3 complex in mental disorders and therapeutic interventions. J. Biomed. Sci.25 (1), 71. 10.1186/s12929-018-0473-x
90
WinterM.SombroekD.DauthI.MoehlenbrinkJ.ScheuermannK.CroneJ.et al (2008). Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nat. Cell Biol.10 (7), 812–824. 10.1038/ncb1743
91
XuM.YuQ.SubrahmanyamR.DifilippantonioM. J.RiedT.SenJ. M. (2008). Beta-catenin expression results in p53-independent DNA damage and oncogene-induced senescence in prelymphomagenic thymocytes in vivo. Mol. Cell. Biol.28 (5), 1713–1723. 10.1128/MCB.01360-07
92
YamamotoT. M.McMellenA.WatsonZ. L.AguileraJ.FergusonR.NurmemmedovE.et al (2019). Activation of Wnt signaling promotes olaparib resistant ovarian cancer. Mol. Carcinog.58 (10), 1770–1782. 10.1002/mc.23064
93
YangY.LeiT.DuS.TongR.WangH.YangJ.et al (2018). Nuclear GSK3β induces DNA double-strand break repair by phosphorylating 53BP1 in glioblastoma. Int. J. Oncol.52 (3), 709–720. 10.3892/ijo.2018.4237
94
YeZ.ShiY.Lees-MillerS. P.TainerJ. A. (2021). Function and molecular mechanism of the DNA damage response in immunity and cancer immunotherapy. Front. Immunol.12, 797880. 10.3389/fimmu.2021.797880
95
ZhangD.WangH.TanY. (2011). Wnt/β-catenin signaling induces the aging of mesenchymal stem cells through the DNA damage response and the p53/p21 pathway. PloS one6 (6), e21397. 10.1371/journal.pone.0021397
96
ZhangY.WangX. (2020). Targeting the Wnt/β-catenin signaling pathway in cancer. J. Hematol. Oncol.13 (1), 165. 10.1186/s13045-020-00990-3
97
ZhaoY.TaoL.YiJ.SongH.ChenL. (2018a). The role of canonical Wnt signaling in regulating radioresistance. Cell. physiology Biochem. Int. J. Exp. Cell. physiology, Biochem. Pharmacol.48 (2), 419–432. 10.1159/000491774
98
ZhaoY.YiJ.TaoL.HuangG.ChuX.SongH.et al (2018b). Wnt signaling induces radioresistance through upregulating HMGB1 in esophageal squamous cell carcinoma. Cell Death Dis.9 (4), 433. 10.1038/s41419-018-0466-4
99
ZhuX.ChenL.HuangB.LiX.YangL.HuX.et al (2021). Efficacy and mechanism of the combination of PARP and CDK4/6 inhibitors in the treatment of triple-negative breast cancer. J. Exp. Clin. Cancer Res.40 (1), 122. 10.1186/s13046-021-01930-w
Summary
Keywords
Wnt, DNA damage response, cancer, therapy, drug resistance
Citation
Zhang X and Yu X (2023) Crosstalk between Wnt/β-catenin signaling pathway and DNA damage response in cancer: a new direction for overcoming therapy resistance. Front. Pharmacol. 14:1230822. doi: 10.3389/fphar.2023.1230822
Received
29 May 2023
Accepted
20 July 2023
Published
02 August 2023
Volume
14 - 2023
Edited by
Ayaz Shahid, Western University of Health Sciences, United States
Reviewed by
Pengcheng Wang, Capital Medical University, China
Mohammad Ashhar I. Khan, University of North Carolina at Chapel Hill, United States
Updates
Copyright
© 2023 Zhang and Yu.
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*Correspondence: Xiaofeng Yu, yanke110112@163.com
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