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Combined WEE1 and ATR inhibition forces mitotic entry of cells with DNA damage. A, MDA-231 and Hs578t cells were treated with the indicated drugs for 48 h. Cells were probed with anti-pHH3 (Ser10) or γH2AX antibodies by flow cytometry. Quantitative data of flow cytometry in upper panel are shown (n = 2, mean ± SD). B, MDA-231 was co-treated with AZD1775 and AZD6738 for 24 h, followed by double staining for p-HH3 (red), or α-tubulin (green) together with DAPI (blue) by immunofluorescence. Scale bar: 10 μm. C, Respective images of typical mitotic phenotypes and several abnormal mitotic phenotypes in pHH3-positive MDA-231 cells are shown. Red, pHH3; green, α-tubulin. D, Quantification of pHH3-positive MDA-231 cells and abnormal mitotic cells in pHH3-positive MDA-231 cells after treatment for 24 h (n = 2, mean ± SD). E, Respective images of normal nuclei and micronuclei are shown. Blue, DAPI. F, Quantification of micronuclei numbers and total nucleuses in MDA-231 and Hs578t cells after treatment for 24 h (n = 2, mean ± SD).
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Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that poses a clinical challenge. Thus, new therapy strategies are urgently needed. The selective WEE1 inhibitor, AZD1775, has shown strong anti-proliferative effects on a variety of tumors. Here, we first demonstrate that inhibition of ATR by selective inhibitor AZ...
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... whether cells with DSBs were pushed into mitosis by probing Those cells that slipped through the unscheduled mitosis had highly cells with anti-pHH3 and anti-γH2AX antibodies. AZD1775 and abnormal nuclear morphology characterized by gross micronuclei, AZD6738 in combination significantly increased the number of mitotic which is a sign of genomic damage events and chromosomal cells after 48 h treatment, and notably almost all the pHH3-positive cells instability [5] (Figure 3, E and F). were γH2AX positive, indicating that the majority of mitotic cells harbored DNA damage ( Figure 3A). ...
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... whether cells with DSBs were pushed into mitosis by probing Those cells that slipped through the unscheduled mitosis had highly cells with anti-pHH3 and anti-γH2AX antibodies. AZD1775 and abnormal nuclear morphology characterized by gross micronuclei, AZD6738 in combination significantly increased the number of mitotic which is a sign of genomic damage events and chromosomal cells after 48 h treatment, and notably almost all the pHH3-positive cells instability [5] (Figure 3, E and F). were γH2AX positive, indicating that the majority of mitotic cells harbored DNA damage ( Figure 3A). ...
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... that CDK1, which triggers mitotic entry by binding There was a striking increase in mitotic cells following combined cyclin B, is inactivated by WEE1. WEE1 phosphorylates its exposure, in comparison with single-drug treatment (Figure 3, B inhibitory phosphorylated site at Tyr15. Conversely, CDC25c and D). ...
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... immunofluorescence images showed that phosphatase can cause the timely activation of CDK1 by dephos premature mitotic cells harbored multiple mitotic abnormalities, phorylating pCDK1 (Tyr15). When DNA is damaged, DDR blocks including but not limited to mono-or multi-polar spindles, CDK1 activity to allow time for DNA damage repair through disorganized spindles, centrosome clustering and cytokinesis failure phosphorylating CHK1 and CHK2 to activate WEE1 and inhibit (Figure 3, C and D). Aberrant mitotic machinery inevitably CDC25c phosphatase [8,16,23]. ...
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... CCK8 assays revealed that low doses of AZD1775 or AZD6738 did not enhance the effect of cisplatin in TNBC cells significantly, but dual exposure to both drugs lead to significant sensitivity to cisplatin ( Figure 5A). Similar observations were also highlighted when cells were treated with veliparib, which is a PARP inhibitor targeting HRR ( Figure S3A). To examine the potential mechanisms underlying these observations, cells were exposed to cisplatin with AZD1775, AZD6738 or both, Figure 4. CDK activities are required for the synergistic cytotoxic effect of combination treatment of AZD1775 and AZD6738 in MDA-231 and Hs578t cells. ...
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... we found that inhibition of AZD1775 and AZD6738 strikingly by transfecting the cells with BRCA1 siRNA to investigate how repressed the cisplatin-induced RAD51 expression, resulting in BRCA1 impairment alone and in combination with AZD1775 or more γH2AX accumulation and pushing more cells into mitosis AZD6738 affected the response to cisplatin and veliparib in the ( Figures 5, B-D and S3B). In a parallel immunofluorescence analysis, BRCA1-wild type MDA-231 and Hs578t cells ( Figure S3C). First, nucleus images illustrated that the addition of AZD1775 and AZD6738 BRCA1 depletion did not sensitize the cells to AZD1775, but it did destroyed the co-localization of RAD51 and γH2AX signals in cells substantially sensitize the cells to the ATR inhibitor AZD6738 following treatment with cisplatin, and led to pan-nucleus γH2AX ( Figure 5F). ...
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... is a key protein in HRR, and notably, BRCA1-related Second, disabled BRCA1 indeed sensitized MDA-231 cells to abnormalities, including BRCA1 mutation and low BRCA1 mRNA cisplatin and veliparib, which is consistent with earlier findings expression, are strictly linked with TNBC [27]. We disabled BRCA1 (Figures 5G and S3D). Third, a combination of AZD1775 and Figure 5. Combined WEE1 and ATR inhibition further sensitizes TNBC cancer cells with defective HRR to cisplatin. ...
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... treatment induced a significant reduction in tumor veliparib, although this enhancement was smaller than that of control growth compared to single drug treatments ( Figure 6A). Additionally, cells ( Figures 5G and S3D). In addition, we observed a similar tendency the single drug or combination treatments did not cause body weight when MDA-231 cells were transfected with lentivirus encoding loss ( Figure 6B). ...
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... addition, we observed a similar tendency the single drug or combination treatments did not cause body weight when MDA-231 cells were transfected with lentivirus encoding loss ( Figure 6B). The TUNEL results of the tumor tissues showed mutational BRCA1 ( Figure S3E). Taken together, combinational compared to the single drugs, combinational WEE1i and ATRi AZD1775 and AZD6738 sensitized the TNBC cells to cisplatin and remarkably increased cell apoptosis ( Figure 6, C and D). ...
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... together, combinational compared to the single drugs, combinational WEE1i and ATRi AZD1775 and AZD6738 sensitized the TNBC cells to cisplatin and remarkably increased cell apoptosis ( Figure 6, C and D). It was also veliparib, independent of the BRCA status, and was demonstrated to confirmed that expression of γH2AX, pRPA32 (S4/S8) and pHH3 further enhance the sensitivity in BRCA1-deficient TNBC cells, which increased in the combination group ( Figures 6E and S3F). highlights its clinical advantages in TNBC patients. ...
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Citations
... Jin et al. demonstrated that inhibition of ATR by ceralasertib in TNBC cell lines can enhance the growth suppression of TNBC by AZD1775, which is a selective WEE1 inhibitor. This response is attributed to suppressed DNA damage repair and excessive replication stress, thereby causing increased DNA damage measured by the accumulation of the DNA DSB marker γH2AX [86]. Ceralasertib showed synergistic efficacy when combined with agents known to induce replication fork stalling and collapse, such as carboplatin and irinotecan, as well as the PARPi olaparib. ...
Simple Summary
Triple-negative breast cancer (TNBC) is recognized for its heightened aggressiveness compared to other breast cancer subtypes. Given the lack of an associated biomarker or molecular target, therapeutic options are limited. In an effort to expand the therapeutic landscape of TNBC, interest has been mounting in the exploitation of the DNA damage response pathway (DDR), particularly with regard to agents that inhibit ATR kinase and Checkpoint Kinases 1/2 (CHK1/2). ATR and CHK1/2 inhibitors show potential as prospective treatment options for TNBC by interfering with the cell cycle regulation of cancer cells. Initial findings indicate that the co-administration of ATR and CHK1/2 inhibitors alongside chemotherapy effectively inhibits tumor growth in TNBC. In this literature review, we explore ATR and CHK1/2 inhibition as a promising therapeutic approach in the management of TNBC and highlight challenges arising during the administration of these novel agents.
Abstract
Worldwide, breast cancer is the most frequently diagnosed malignancy in women, with triple-negative breast cancer (TNBC) being the most aggressive molecular subtype. Due to the dearth of effective therapeutic options for TNBC, novel agents targeting key mechanisms and pathways in cancer cells are continuously explored; these include ATR inhibitors, which target the ATR kinase involved in the DNA damage response (DDR) pathway, and CHK1/2 inhibitors, which target the Checkpoint Kinase 1/2 (CHK1/2) involved in cell cycle arrest and DNA repair. ATR and CHK1/2 inhibitors show potential as prospective treatments for TNBC by focusing on the DDR and interfering with cell cycle regulation in cancer cells. Preliminary preclinical and clinical findings suggest that when combined with chemotherapy, ATR and CHK1/2 inhibitors demonstrate significant anti-proliferative efficacy against TNBC. In this article, we introduce ATR and CHK1/2 inhibitors as promising therapeutic approaches for the management of TNBC. Preclinical and clinical studies performed evaluating ATR and CHK1/2 inhibitors for the treatment of TNBC and associated challenges encountered in this context to date are reviewed.
... 126 Thus, this study offers a new scope for further optimization. A few analogues of pyrazolopyr-imidine (80−83) and pyrrolopyrimide (84,85), along with their inhibitory constant values, are incorporated in Figure 15. ...
WEE1 is a checkpoint kinase critical for mitotic events, especially in cell maturation and DNA repair. Most cancer cells' progression and survival are linked with elevated levels of WEE1 kinase. Thus, WEE1 kinase has become a new promising druggable target. A few classes of WEE1 inhibitors are designed by rationale or structure-based techniques and optimization approaches to identify selective acting anticancer agents. The discovery of the WEE1 inhibitor AZD1775 further emphasized WEE1 as a promising anticancer target. Therefore, the current review provides a comprehensive data on medicinal chemistry, synthetic approaches, optimization methods, and the interaction profile of WEE1 kinase inhibitors. In addition, WEE1 PROTAC degraders and their synthetic procedures, including a list of noncoding RNAs necessary for regulation of WEE1, are also highlighted. From the standpoint of medicinal chemistry, the contents of this compilation serve as an exemplar for the further design, synthesis, and optimization of promising WEE1-targeted anticancer agents.
... Earlier research has demonstrated that in small-cell lung cancer, the activation of Chk1 through the upregulation of AXL and MET pathways is a significant mechanism of resistance to AZD-1775 [47]. Thus, combining ATR with Chk1 inhibition can be a rational approach to overcoming resistance to Wee1 inhibition, and it has demonstrated a synergistic anti-tumor effect in multiple types of cancer cells [48][49][50]. While the application of ATR inhibitors in urothelial carcinoma is still in its early stages of research, a potential new therapeutic approach involves combining Wee1 and ATR inhibition with conventional platinum-based chemotherapy. ...
Urothelial carcinoma (UC) is characterized by a high incidence of TP53 mutation, and overcoming resistance to cisplatin-based chemotherapy in UC is a major concern. Wee1 is a G2/M phase regulator that controls the DNA damage response to chemotherapy in TP53-mutant cancers. The combination of Wee1 blockade with cisplatin has shown synergistic efficacy in several types of cancers, but little is known regarding UC. The antitumor efficacy of the Wee1 inhibitor (AZD-1775) alone or in combination with cisplatin was evaluated in UC cell lines and a xenograft mouse model. AZD-1775 enhanced the anticancer activity of cisplatin by increasing cellular apoptosis. AZD-1775 inhibited the G2/M checkpoint, improving the sensitivity of mutant TP53 UC cells to cisplatin by enhancing the DNA damage process. We confirmed that AZD-1775 combined with cisplatin reduced tumor volume and proliferation activity and increased the markers of cell apoptosis and DNA damage in the mouse xenograft model. In summary, the Wee1 inhibitor AZD-1775 combined with cisplatin elicited a promising anticancer efficacy in UC, and constitutes an innovative and promising therapeutic strategy.
... The interaction between ATRi and CHK1i has been demonstrated previously using established cell lines (64,65). In addition, the ATRi-WEE1i combination is synergistic in acute myeloid leukemia, breast, and biliary tract cancer models (84)(85)(86)(87). We extend these findings, showing that these two-drug combinations are synergistic in patient-derived models of ovarian cancer, and that they are effective at relatively low concentrations. ...
High-grade serous ovarian cancer (HGSOC) is an aggressive disease that typically develops drug resistance, thus novel biomarker-driven strategies are required. Targeted therapy focuses on synthetic lethality—pioneered by PARP inhibition of BRCA1/2-mutant disease. Subsequently, targeting the DNA replication stress response (RSR) is of clinical interest. However, further mechanistic insight is required for biomarker discovery, requiring sensitive models that closely recapitulate HGSOC. We describe an optimized proliferation assay that we use to screen 16 patient-derived ovarian cancer models (OCMs) for response to RSR inhibitors (CHK1i, WEE1i, ATRi, PARGi). Despite genomic heterogeneity characteristic of HGSOC, measurement of OCM proliferation was reproducible and reflected intrinsic tumour-cell properties. Surprisingly, RSR targeting drugs were not interchangeable, as sensitivity to the four inhibitors was not correlated. Therefore, to overcome RSR redundancy, we screened the OCMs with all two-, three- and four-drug combinations in a multiple-low-dose strategy. We found that low-dose CHK1i-ATRi had a potent anti-proliferative effect on 15 of the 16 OCMs, and was synergistic with potential to minimise treatment resistance and toxicity. Low-dose ATRi-CHK1i induced replication catastrophe followed by mitotic exit and post-mitotic arrest or death. Therefore, this study demonstrates the potential of the living biobank of OCMs as a drug discovery platform for HGSOC.
... Recently, a phase 2 clinical trial demonstrated that the WEE1 inhibitor adavosertib combined with cisplatin improved clinical outcomes for patients with metastatic TNBC [110]. Interestingly, dual inhibition of WEE1 and ATR sensitizes TNBC cells to cisplatin and PARP inhibitors [111], extending the catalog of possible combinations with other targeted inhibitors that could be implemented. ...
Proliferating cells rely on DNA replication to ensure accurate genome duplication. Cancer cells, including breast cancer cells, exhibit elevated replication stress (RS) due to the uncontrolled oncogenic activation, loss of key tumor suppressors, and defects in the DNA repair machinery. This intrinsic vulnerability provides a great opportunity for therapeutic exploitation. An increasing number of drug candidates targeting RS in breast cancer are demonstrating promising efficacy in preclinical and early clinical trials. However, unresolved challenges lie in balancing the toxicity of these drugs while maintaining clinical efficacy. Furthermore, biomarkers of RS are urgently required to guide patient selection. In this review, we introduce the concept of targeting RS, detail the current therapies that target RS, and highlight the integration of RS with immunotherapies for breast cancer treatment. Additionally, we discuss the potential biomarkers to optimizing the efficacy of these therapies. Together, the continuous advances in our knowledge of targeting RS would benefit more patients with breast cancer.
... One more inhibitor, namely Icariin, has been shown to retard the expression of CDK2 and CDK4 in those MCF7/TAM cell lines which are resistant to tamoxifen-resistant [94]. AZD1775, Tyrosine kinase WEE1 inhibitor, combined with AZD6738, results in cell death [95]. One specific CDK1 inhibitor, namely, methyl2-(-5-fluoro-2-hydroxyphenyl)-1H-benzo imidazole-5-carboxylate (MBIC) is associated with p53 expression and can result in cell death [96]. ...
Presently, breast cancer (BC) is one of the most common malignancies diagnosed and the leading cause of tumor-related deaths among women worldwide. Cell cycle dysregulation is one of the hallmarks of cancer, resulting in uncontrolled cell proliferation. Cyclin-dependent kinases (CDKs) are central to the cell cycle control system, and deregulation of these kinases leads to the development of malignancies, including breast cancer. CDKs and cyclins have been reported as crucial components involved in tumor cell proliferation and metastasis. Given the aggressive nature, tumor heterogeneity, and chemoresistance, there is an urgent need to explore novel targets and therapeutics to manage breast cancer effectively. Inhibitors targeting CDKs modulate the cell cycle, thus throwing light upon their therapeutic aspect where the progression of tumor cells could be inhibited. This article gives a comprehensive account of CDKs in breast cancer progression and metastasis and recent developments in the modulation of CDKs in treating malignancies. We have also explored the expression pattern and prognostic significance of CDKs in breast cancer patients. The article will also shed light on the Implications of CDK inhibition and TGF-β signaling in breast cancer.
Graphical abstract
... Interestingly, recent studies achieved effective results in the treatment of TNBC through combination therapy alone or in parallel with chemotherapy. ATR inhibitor AZD6738 and WEE1 inhibitor AZD1775 inactivated RAD51-mediated homologous recombination [359], activated cyclin-dependent kinase 1 (CDK1) activity, forced DNA-damaged cells into mitosis, and induced serious mitotic abnormalities and mitotic catastrophes, eventually resulting in TNBC cell death, and improving the sensitivity of TNBC to cisplatin and PARP inhibitors [360,361]. BMS-754807, as a dual IGF-1R/InsR inhibitor, combined with the chemotherapeutic drug docetaxel could increase cell apoptosis and induce mitotic catastrophe, inhibit the growth of TNBC primary human tumor transplantation MC1, and regress tumors [362]. Additionally, the combination of IGF-1R inhibitor NVP-AEW541 and autophagy inhibitor 3-mA could improve the therapeutic effect of IGF-1R inhibitors in TNBC cells, which provided a direction for the combined treatment strategy based on IGF-1R inhibitors [363]. ...
Triple-negative breast cancer (TNBC) is a subtype of human breast cancer with one of the worst prognoses, with no targeted therapeutic strategies currently available. Regulated cell death (RCD), also known as programmed cell death (PCD), has been widely reported to have numerous links to the progression and therapy of many types of human cancer. Of note, RCD can be divided into numerous different subroutines, including autophagy-dependent cell death, apoptosis, mitotic catastrophe, necroptosis, ferroptosis, pyroptosis and anoikis. More recently, targeting the subroutines of RCD with small-molecule compounds has been emerging as a promising therapeutic strategy, which has rapidly progressed in the treatment of TNBC. Therefore, in this review, we focus on summarizing the molecular mechanisms of the above-mentioned seven major RCD subroutines related to TNBC and the latest progress of small-molecule compounds targeting different RCD subroutines. Moreover, we further discuss the combined strategies of one drug (e.g., narciclasine) or more drugs (e.g., torin-1 combined with chloroquine) to achieve the therapeutic potential on TNBC by regulating RCD subroutines. More importantly, we demonstrate several small-molecule compounds (e.g., ONC201 and NCT03733119) by targeting the subroutines of RCD in TNBC clinical trials. Taken together, these findings will provide a clue on illuminating more actionable low-hanging-fruit druggable targets and candidate small-molecule drugs for potential RCD-related TNBC therapies.
Graphical abstract
... Importantly, the phosphorylation state of CDKs 1 and 2 (and thus their inhibition) is regulated by the balance between the kinase activity of Wee1 (and Myt1) and the phosphatase activity of Cdc25. The observed synergistic effects of Wee1 and ATR inhibition (71,115) on cancer cell killing are surely in grant part due to the lowering of the threshold for CDK activation by combining inhibiting the constitutive phosphorylation and preventing checkpoint activation by the ATR/CHK1/Cdc25 axis, as combined AZD1775 and AZD6738 treatment leads to mitotic catastrophe in cancer cells (71). Yet both Wee1 and ATR regulate other cellular aspects that will play a role, including their activities during replication: For example, the above mentioned role of Wee1 during S phase, including replication fork protection, as well as reportedly in timing the entry into S phase (116) are perturbed by AZD1775 and lead to substantial replication stress. ...
Cancer cells typically heavily rely on the G2/M checkpoint to survive endogenous and exogenous DNA damage, such as genotoxic stress due to genome instability or radiation and chemotherapy. The key regulator of the G2/M checkpoint, the cyclin-dependent kinase 1 (CDK1), is tightly controlled, including by its phosphorylation state. This posttranslational modification, which is determined by the opposing activities of the phosphatase cdc25 and the kinase Wee1, allows for a more rapid response to cellular stress than via the synthesis or degradation of modulatory interacting proteins, such as p21 or cyclin B. Reducing Wee1 activity results in ectopic activation of CDK1 activity and drives premature entry into mitosis with unrepaired or under-replicated DNA and causing mitotic catastrophe. Here, we review efforts to use small molecule inhibitors of Wee1 for therapeutic purposes, including strategies to combine Wee1 inhibition with genotoxic agents, such as radiation therapy or drugs inducing replication stress, or inhibitors of pathways that show synthetic lethality with Wee1. Furthermore, it become increasingly clear that Wee1 inhibition can also modulate therapeutic immune responses. We will discuss the mechanisms underlying combination treatments identifying both cell intrinsic and systemic anti-tumor activities.
... The absence of human epidermal growth factor receptor 2 (Her2) and both the estrogen and progesterone receptors are characteristic of this disease. This presents a major therapeutic challenge, due to the absence of a suitable endocrine therapy or effective target therapy [2,3]. Therefore, surgery and chemotherapy, either individually or in combination, remain the only available treatment interventions [4]. ...
... It is suggested that the CRIF1-CDK2 interface inhibitor could improve cellular radio sensitivity in the osteosarcoma (OS) cell lines by selectively enhancing arrest in the G2/M phase and apoptosis associated with CDK2 overactivation in these cells [16]. On the other hand, although recent evidence points towards key negative regulators of CDKs as therapeutic targets in TNBC, a number of CDK inhibitors have undergone evaluation in clinical trials, but yielded disappointing results because of their low specificity to target specific CDK enzymes [3,17]. Therefore, more specific, and potent inhibitors, targeting CDK enzymes, are urgently needed for the treatment of TNBC. ...
... Normal CDKs inhibitors target CDKs, such as CDK4/6, directly to regulate the cell cycle, decreasing the cell proliferation by arresting cells in the G0/G1 or G2/M checkpoints [11,12,31]. However, numerous CDK inhibitors have indicated low specificity and selectivity to targetspecific CDK enzymes [3,17]. The CRIF1-CDK2 interface inhibitors show benefits to the specificity and selectivity of treatment because they target CRIF1 and CDK interfaces, thus indirectly modulating the cell cycle and apoptosis and increasing the cancer cell sensitivity to chemotherapy. ...
Simple Summary
This study reported our most recent results for targeting triple-negative breast cancer (TNBC) with a low survival rate, using CR6-interacting factor 1–cyclin-dependent kinase 2 (CRIF1–CDK2) interface inhibitors, by inhibiting the resistance to taxol treatment. Presently, over 50% of TNBC patients become resistant to chemotherapy and, to date, no solution is available. The combined treatment, using CRIF1–CDK2 interface inhibitors with chemotherapy, provides an unprecedented strategy against the deadly TNBC.
Abstract
Paclitaxel (taxol), a chemotherapeutic agent, remains the standard of care for the lethal triple-negative breast cancer (TNBC). However, over 50% of TNBC patients become resistant to chemotherapy and, to date, no solution is available. CR6-interacting factor 1 (CRIF1) is reported to act as a negative regulator of the cell cycle by interacting with cyclin-dependent kinase 2 (CDK2). In our study, two selective CRIF1–CDK2 interface inhibitors were used to investigate whether they could exert anti-proliferative activity on the TNBC cell lines. When combined with taxol treatment, these two inhibitors can advance the cells from G0/G1 to S and G2/M phases, producing irreparable damage to the cells, which then undergo apoptosis. Moreover, they enhanced the reduction in cell proliferation induced by taxol in TNBC cells, thereby improving sensitivity to taxol in these cell lines. Importantly, the inhibitors did not regulate the cell cycle in normal cells, indicating their high selectivity towards TNBC cells. Overall, the resistance to the anti-proliferative effects induced by taxol can be significantly reduced by the combined treatment with selective CRIF1–CDK2 interface inhibitors, making a conceptual advance in the CDK-related cancer treatment.
... If the M phase begins, this damage will result in the loss of part of the DNA [110]. Other [138] (continued on next page) types of damage include, single strand break (SSB) and changes in the nucleotide structure (oxidative damage) [111]. Detection of DNA damage is performed by two major ATM and ATR sensors, which are both protein kinases (Fig. 3) [112]. ...
... The study also demonstrated that the combination of AZD1775 and AZD6738 further increased the ability of cisplatin to induce cell death. Finally, a synergistic effect was observed between WEE1 inhibition and ATR inhibition as a future TNBC treatment (Table 2) [138]. ...
Mitosis is the process of cell division and is regulated by checkpoints in the cell cycle. G1-S, S, and G2-M are the three main checkpoints that prevent initiation of the next phase of the cell cycle phase until previous phase has completed. DNA damage leads to activation of the G2-M checkpoint, which can trigger a downstream DNA damage response (DDR) pathway to induce cell cycle arrest while the damage is repaired. If the DNA damage cannot be repaired, the replication stress response (RSR) pathway finally leads to cell death by apoptosis, in this case called mitotic catastrophe. Many cancer treatments (chemotherapy and radiotherapy) cause DNA damages based on SSBs (single strand breaks) or DSBs (double strand breaks), which cause cell death through mitotic catastrophe. However, damaged cells can activate WEE1 kinase (as a part of the DDR and RSR pathways), which prevents apoptosis and cell death by inducing cell cycle arrest at G2 phase. Therefore, inhibition of WEE1 kinase could sensitize cancer cells to chemotherapeutic drugs. This review focuses on the role of WEE1 kinase (as a biological macromolecule which has a molecular mass of 96 kDa) in the cell cycle, and its interactions with other regulatory pathways. In addition, we discuss the potential of WEE1 inhibition as a new therapeutic approach in the treatment of various cancers, such as melanoma, breast cancer, pancreatic cancer, cervical cancer, etc.
