Author
Yasuhisa Murai
Bio: Yasuhisa Murai is an academic researcher from Hirosaki University. The author has contributed to research in topics: Medicine & Colitis. The author has an hindex of 4, co-authored 11 publications receiving 34 citations.
Topics: Medicine, Colitis, DNA damage, Chemistry, Capsule endoscopy
Papers
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TL;DR: In this article, a new ATR-based chemotherapy drug, M4344, was proposed and compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib using in vitro and in vivo models.
Abstract: Although several ATR inhibitors are in development, there are unresolved questions regarding their differential potency, molecular signatures of patients with cancer for predicting activity, and most effective therapeutic combinations Here, we elucidate how to improve ATR-based chemotherapy with the newly developed ATR inhibitor, M4344 using in vitro and in vivo models The potency of M4344 was compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib The anticancer activity of M4344 was investigated as monotherapy and combination with clinical DNA damaging agents in multiple cancer cell lines, patient-derived tumor organoids, and mouse xenograft models We also elucidated the anticancer mechanisms and potential biomarkers for M4344 We demonstrate that M4344 is highly potent among the clinically developed ATR inhibitors Replication stress (RepStress) and neuroendocrine (NE) gene expression signatures are significantly associated with a response to M4344 treatment M4344 kills cancer cells by inducing cellular catastrophe and DNA damage M4344 is highly synergistic with a broad range of DNA-targeting anticancer agents It significantly synergizes with topotecan and irinotecan in patient-derived tumor organoids and xenograft models Taken together, M4344 is a promising and highly potent ATR inhibitor It enhances the activity of clinical DNA damaging agents commonly used in cancer treatment including topoisomerase inhibitors, gemcitabine, cisplatin, and talazoparib RepStress and NE gene expression signatures can be exploited as predictive markers for M4344
41 citations
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TL;DR: In this paper, the authors performed an unbiased genome-wide RNAi screen in SLFN11-WT and -knockout (KO) cells and found that inactivation of Ataxia Telangiectasia- and Rad3-related (ATR), CHK1, BRCA2, and RPA1 overcome chemoresistance to camptothecin (CPT) in cancer cells.
Abstract: Schlafen-11 (SLFN11) inactivation in ∼50% of cancer cells confers broad chemoresistance To identify therapeutic targets and underlying molecular mechanisms for overcoming chemoresistance, we performed an unbiased genome-wide RNAi screen in SLFN11-WT and -knockout (KO) cells We found that inactivation of Ataxia Telangiectasia- and Rad3-related (ATR), CHK1, BRCA2, and RPA1 overcome chemoresistance to camptothecin (CPT) in SLFN11-KO cells Accordingly, we validate that clinical inhibitors of ATR (M4344 and M6620) and CHK1 (SRA737) resensitize SLFN11-KO cells to topotecan, indotecan, etoposide, cisplatin, and talazoparib We uncover that ATR inhibition significantly increases mitotic defects along with increased CDT1 phosphorylation, which destabilizes kinetochore-microtubule attachments in SLFN11-KO cells We also reveal a chemoresistance mechanism by which CDT1 degradation is retarded, eventually inducing replication reactivation under DNA damage in SLFN11-KO cells In contrast, in SLFN11-expressing cells, SLFN11 promotes the degradation of CDT1 in response to CPT by binding to DDB1 of CUL4CDT2 E3 ubiquitin ligase associated with replication forks We show that the C terminus and ATPase domain of SLFN11 are required for DDB1 binding and CDT1 degradation Furthermore, we identify a therapy-relevant ATPase mutant (E669K) of the SLFN11 gene in human TCGA and show that the mutant contributes to chemoresistance and retarded CDT1 degradation Taken together, our study reveals new chemotherapeutic insights on how targeting the ATR pathway overcomes chemoresistance of SLFN11-deficient cancers It also demonstrates that SLFN11 irreversibly arrests replication by degrading CDT1 through the DDB1-CUL4CDT2 ubiquitin ligase
25 citations
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TL;DR: In this article, the authors conducted a drug screen with the NCATS mechanistic drug library of 1,978 compounds in isogenic SLFN11-knockout (KO) and wild-type (WT) leukemia cell lines and found that TAK-243, a first-in-class ubiquitin activating enzyme UBA1 inhibitor in clinical development, causes preferential cytotoxicity in SLFN-11-KO cells; this effect is associated with claspin-mediated DNA replication inhibition by CHK1 independently of ATR.
Abstract: Schlafen11 (SLFN11) inactivation occurs in approximately 50% of cancer cell lines and in a large fraction of patient tumor samples, which leads to chemoresistance. Therefore, new therapeutic approaches are needed to target SLFN11-deficient cancers. To that effect, we conducted a drug screen with the NCATS mechanistic drug library of 1,978 compounds in isogenic SLFN11-knockout (KO) and wild-type (WT) leukemia cell lines. Here we report that TAK-243, a first-in-class ubiquitin activating enzyme UBA1 inhibitor in clinical development, causes preferential cytotoxicity in SLFN11-KO cells; this effect is associated with claspin-mediated DNA replication inhibition by CHK1 independently of ATR. Additional analyses showed that SLFN11-KO cells exhibit consistently enhanced global protein ubiquitylation, endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and protein aggregation. TAK-243 suppressed global protein ubiquitylation and activated the UPR transducers PERK, phosphorylated eIF2α, phosphorylated IRE1, and ATF6 more effectively in SLFN11-KO cells than in WT cells. Proteomic analysis using biotinylated mass spectrometry and RNAi screening also showed physical and functional interactions of SLFN11 with translation initiation complexes and protein folding machinery. These findings uncover a previously unknown function of SLFN11 as a regulator of protein quality control and attenuator of ER stress and UPR. Moreover, they suggest the potential value of TAK-243 in SLFN11-deficient tumors. SIGNIFICANCE: This study uncovers that SLFN11 deficiency induces proteotoxic stress and sensitizes cancer cells to TAK-243, suggesting that profiling SLFN11 status can serve as a therapeutic biomarker for cancer therapy.
21 citations
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TL;DR: In this paper, the role of Spartan (SPRTN) is explored for DNA replication in human TK6 and chicken DT40 lymphoblastoid cells, and it is shown that SPRTN-deficient cells are hypersensitive to talazoparib and olaparib, but not to veliparib.
Abstract: The antitumor activity of poly(ADP-ribose) polymerase inhibitors (PARPis) has been ascribed to PARP trapping, which consists in tight DNA-protein complexes. Here we demonstrate that the cytotoxicity of talazoparib and olaparib results from DNA replication. To elucidate the repair of PARP1-DNA complexes associated with replication in human TK6 and chicken DT40 lymphoblastoid cells, we explored the role of Spartan (SPRTN), a metalloprotease associated with DNA replication, which removes proteins forming DPCs. We find that SPRTN-deficient cells are hypersensitive to talazoparib and olaparib, but not to veliparib, a weak PARP trapper. SPRTN-deficient cells exhibit delayed clearance of trapped PARP1 and increased replication fork stalling upon talazoparib and olaparib treatment. We also show that SPRTN interacts with PARP1 and forms nuclear foci that colocalize with the replicative cell division cycle 45 protein (CDC45) in response to talazoparib. Additionally, SPRTN is deubiquitinated and epistatic with translesion synthesis (TLS) in response to talazoparib. Our results demonstrate that SPRTN is recruited to trapped PARP1 in S-phase to assist in the excision and replication bypass of PARP1-DNA complexes.
15 citations
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TL;DR: An insight is provided into the interplay between m6A modification and ncRNAs in cancer by identifying regulators that can target or modulate m 6A regulators to influence cancer development.
Abstract: N6-methyladenosine (m6A) is one of the most common RNA modifications in eukaryotes, mainly in messenger RNA (mRNA). Increasing evidence shows that m6A methylation modification acts an essential role in various physiological and pathological bioprocesses. Noncoding RNAs (ncRNAs), including miRNAs, lncRNAs and circRNAs, are known to participate in regulating cell differentiation, angiogenesis, immune response, inflammatory response and carcinogenesis. m6A regulators, such as METTL3, ALKBH5 and IGF2BP1 have been reported to execute a m6A-dependent modification of ncRNAs involved in carcinogenesis. Meanwhile, ncRNAs can target or modulate m6A regulators to influence cancer development. In this review, we provide an insight into the interplay between m6A modification and ncRNAs in cancer.
133 citations
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TL;DR: ICI-induced IA can become a long-term disease necessitating management by rheumatology for immunomodulatory treatment, and the use of immunosuppressants has not been shown to impact cancer outcomes in this study.
Abstract: Objective We sought to investigate the long-term outcomes of patients who develop immune checkpoint inhibitor (ICI)-induced inflammatory arthritis (IA), to define factors associated with IA persistence after ICI cessation, the need for immunosuppressants and the impact of these medications on underlying malignancies. Methods We conducted a prospective observational study of patients referred for IA associated with ICIs. Patients were recruited from June 2015 to December 2018. Information was obtained at the baseline visit, and follow-up visits occurred at varying intervals for up to 24 months from ICI cessation. Kaplan-Meier curves were developed to characterise IA persistence. Cox proportional hazards models were used to assess the influence of various factors on IA persistence. Logistic regression was used to evaluate the impact of IA treatment on tumour response. Results Sixty patients were monitored with a median follow-up after ICI cessation of 9 months. A majority (53.3%) had active IA at their most recent follow-up. IA was less likely to improve in those with longer duration of ICI use, in those receiving combination ICI therapy, and in patients with multiple other immune-related adverse events. Tumour response did not appear to be impacted by immunosuppression. Although not statistically significant, persistent IA was correlated with a better tumour response (complete or partial response). Conclusion ICI-induced IA can become a long-term disease necessitating management by rheumatology for immunomodulatory treatment. Importantly, the use of immunomodulatory treatment has not been shown to impact cancer outcomes in this study.
129 citations
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TL;DR: This review summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.
Abstract: Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.
79 citations
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TL;DR: In most studies, H19 knockdown via RNA interference (RNAi) or epigenetic silencing inhibits cancer development, which makes H19 lncRNA a promising target for the development of cancer therapeutics.
44 citations
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TL;DR: In this article, a new ATR-based chemotherapy drug, M4344, was proposed and compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib using in vitro and in vivo models.
Abstract: Although several ATR inhibitors are in development, there are unresolved questions regarding their differential potency, molecular signatures of patients with cancer for predicting activity, and most effective therapeutic combinations Here, we elucidate how to improve ATR-based chemotherapy with the newly developed ATR inhibitor, M4344 using in vitro and in vivo models The potency of M4344 was compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib The anticancer activity of M4344 was investigated as monotherapy and combination with clinical DNA damaging agents in multiple cancer cell lines, patient-derived tumor organoids, and mouse xenograft models We also elucidated the anticancer mechanisms and potential biomarkers for M4344 We demonstrate that M4344 is highly potent among the clinically developed ATR inhibitors Replication stress (RepStress) and neuroendocrine (NE) gene expression signatures are significantly associated with a response to M4344 treatment M4344 kills cancer cells by inducing cellular catastrophe and DNA damage M4344 is highly synergistic with a broad range of DNA-targeting anticancer agents It significantly synergizes with topotecan and irinotecan in patient-derived tumor organoids and xenograft models Taken together, M4344 is a promising and highly potent ATR inhibitor It enhances the activity of clinical DNA damaging agents commonly used in cancer treatment including topoisomerase inhibitors, gemcitabine, cisplatin, and talazoparib RepStress and NE gene expression signatures can be exploited as predictive markers for M4344
41 citations