WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance

Zheng, Huakun; Shao, Fangyuan; Martin, Scots; Xu, Xiaoling; Deng, Chu‐Xia

doi:10.1038/srep43517

Cited by 49 publications

(46 citation statements)

References 54 publications

(99 reference statements)

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“…Our loss-of-function genetic screen allowed showing that the kinase ATR is, at least in part, responsible of this resistance, and suggests that the ATRi and oxaliplatin combination therapy could be useful in the clinic. Similar screenings have already demonstrated that ATR, CHK1, and WEE1 are involved in the sensitivity to cisplatin in triplenegative breast cancer (36). Moreover, ATR inhibition sensitized cancer cells to chemotherapy, for instance in ovarian cancer (in combination with cisplatin and gemcitabine), in pancreatic cancer (with gemcitabine), in breast cancer (with camptothecin) and in lung cancer (with cisplatin, oxaliplatin, gemcitabine, etoposide, and SN38; ref.…”

Section: Discussionsupporting

confidence: 63%

Inhibition of Ataxia-Telangiectasia Mutated and RAD3-Related (ATR) Overcomes Oxaliplatin Resistance and Promotes Antitumor Immunity in Colorectal Cancer

et al. 2019

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Immune cell death IFN production Antitumoral immunity Oxaliplatin + ATRi Cell autonomous cell death Cytoplasmic DNA Proliferation inhibition Apoptosis induction DNA damage Replication stress Although many patients with colorectal cancer initially respond to the chemotherapeutic agent oxaliplatin, acquired resistance to this treatment remains a major challenge to the long-term management of this disease. To identify molecular targets of oxaliplatin resistance in colorectal cancer, we performed an shRNA-based loss-of-function genetic screen using a kinome library. We found that silencing of ataxia-telangiectasia mutated and RAD3-related (ATR), a serine/threonine protein kinase involved in the response to DNA stress, restored oxaliplatin sensitivity in a cellular model of oxaliplatin resistance. Combined application of the ATR inhibitor VE-822 and oxaliplatin resulted in strong synergistic effects in six different colorectal cancer cell lines and their oxaliplatin-resistant subclones, promoted DNA single-and double-strand break formation, growth arrest, and apoptosis. This treatment also increased replicative stress, cytoplasmic DNA, and signals related to immunogenic cell death such as calreticulin exposure and HMGB1 and ATP release. In a syngeneic colorectal cancer mouse model, combined administration of VE-822 and oxaliplatin significantly increased survival by promoting antitumor T-cell responses. Finally, a DNA repair gene signature discriminated sensitive from drug-resistant patients with colorectal cancer. Overall, our results highlight the potential of ATR inhibition combined with oxaliplatin to sensitize cells to chemotherapy as a therapeutic option for patients with colorectal cancer. Significance: These findings demonstrate that resistance to oxaliplatin in colorectal cancer cells can be overcome with inhibitors of ATR and that combined treatment with both agents exerts synergistic antitumor effects.

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Section: Discussionsupporting

confidence: 63%

Inhibition of Ataxia-Telangiectasia Mutated and RAD3-Related (ATR) Overcomes Oxaliplatin Resistance and Promotes Antitumor Immunity in Colorectal Cancer

et al. 2019

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“…Recent studies have reported the sensitivity of TNBC to WEE1 targeting in the presence of either PARP or ATR inhibitors, or Cisplatin. [17,19,20,22,41] However, we found that MMTV-R26 Met MGT cells were either resistant or only partially sensitive to these drug combinations ( Figure 5E), recapitulating other mechanisms of primary resistance beside those reported in Figure 3G-H. Thus, BCL-XL targeting is a preferable strategy to exacerbate WEE1 essentiality in TNBC.…”

Section: Combined Targeting Of Wee1 and Bcl-xl Is Deleterious For Tnbmentioning

confidence: 63%

“…Co-inhibition of WEE1 with either radiotherapy or anticancer drugs such as cisplatin, gemcitabin, paclitaxel, or inhibitors of CDC25, ATR, or PARP causes death of breast cancer cells. [15][16][17][18][19][20][21][22] The rational of these combined treatments is to associate DNA-damaging therapies together with perturbation of DNA damage checkpoint gatekeepers through WEE1 targeting. Nevertheless, the consequences of WEE1 targeting may be broader than cell cycle regulation, in view of recent studies showing that WEE1 inactivation increases CDK-dependent firing of dormant replication origins thereby leading to replication stress and increased dNTP demand.…”

Section: Introductionmentioning

confidence: 99%

Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance

Lamballe

Ahmad

Vinik

et al. 2020

Preprint

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Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity and resistance to treatment. Here, we report the generation of a unique mouse model (MMTV-R26 Met mice) in which a subtle increase in the expression levels of the wild-type MET receptor tyrosine kinase leads to spontaneous, exclusive TNBC formation, recapitulating TNBC heterogeneity. We further exploited the MMTV-R26 Met TNBC model by exploring signaling alterations through proteomics to search for TNBC vulnerability. We identified a new drug combination based on combinatorial targeting of WEE1 and BCL-XL that efficiently kills TNBC cells. Mechanistically, we show that BCL-XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS 33 RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, and depletion of oncogenic signals, resulting in mitotic catastrophe and apoptosis. Our findings suggest that combination therapy with BCL-XL and WEE1 inhibitors warrants further evaluation in clinical trials. Statement of significanceWe have developed a new TNBC mouse model that recapitulates resistance to chemotherapy and heterogeneity. We uncovered that combined inhibition of WEE1 and BCL-XL selectively kills mouse and human TNBC cells, and provided mechanistic insights underlying this combined targeting. We propose that BCL-XL inhibition exacerbates WEE1 requirement for TNBC survival. cancer subtypes, TNBC is characterized by the earliest age of onset, a higher prevalence in African-Americans, a high propensity for metastasis, and the worst prognosis in terms of relapse and survival rate (6,7). Over 80% of TNBC patients exhibit alterations in the TP53 locus (8), whereas a smaller fraction has mutations in genes controlling the PI3K pathway and homologous recombination including BRCA1/2 negative. A molecular feature of TNBC is the dependency of cancer cells on signals that are rarely mutated, a phenomenon defined as "non-oncogene addiction" (9). It is the case, for example, of components of the receptor tyrosine kinase (RTK) core pathway (7,10). Collectively, these traits are 4 among the leading cause of limited efficacy of current TNBC therapies. Radiation therapy and chemotherapy, applied before and after surgery, are the mainstay of treatment, although frequently associated with drug resistance and recurrent disease.Extensive efforts have been made to search for molecular targeted therapies effective for TNBC treatment. Although some targeted therapies approved for treatment of other cancer types have been proposed in TNBC, they rarely turned out to be clinically relevant (11). These limited responses are associated with the high heterogeneity of the disease and the lack of suitable immunocompetent preclinical models that recapitulate the molecular diversity of TNBC. Among potential targets for TNBC subsets are PARP1, androgen receptor (AR), vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR...

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“…In triple-negative breast cancer, WEE1 inhibition overcame cisplatin resistance by disrupting DNA replication and G2/ M cell cycle checkpoint regulation [20]. A clinical trial also revealed that BTC patients harboring DDR-related gene mutations responded better to cisplatin therapy than those with wild-type cancer [21].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer

et al. 2020

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Original ArticlePurpose Currently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC. Materials and MethodsIn this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models. ResultsAZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy. ConclusionTaken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC.

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WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance

Cited by 49 publications

References 54 publications

Inhibition of Ataxia-Telangiectasia Mutated and RAD3-Related (ATR) Overcomes Oxaliplatin Resistance and Promotes Antitumor Immunity in Colorectal Cancer

Inhibition of Ataxia-Telangiectasia Mutated and RAD3-Related (ATR) Overcomes Oxaliplatin Resistance and Promotes Antitumor Immunity in Colorectal Cancer

Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance

Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer

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