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Clint T Allen - One of the best experts on this subject based on the ideXlab platform.
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enhancing direct cytotoxicity and response to immune Checkpoint blockade following ionizing radiation with wee1 kinase inhibition
OncoImmunology, 2019Co-Authors: Priya Patel, Paul E Clavijo, Carter Van Waes, Jay Friedman, Yvette Robbins, Christopher Silvin, John A Cook, James B Mitchell, Clint T AllenAbstract:ABSTRACTTumor Cells activate the G2/M Cell Cycle Checkpoint in response to ionizing radiation (IR) and effector immune Cell-derived granzyme B to facilitate repair and survival. Wee1 kinase inhibit...
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wee1 kinase inhibition reverses g2 m Cell Cycle Checkpoint activation to sensitize cancer Cells to immunotherapy
OncoImmunology, 2018Co-Authors: Ellen C Moore, Rose Berman, Paul E Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T AllenAbstract:Intrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M Cell Cycle Checkpoint results in tumor Cell Cycle pause and protection from granzyme B-induced Cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor Cells. Similarly, but at a later time point, Cell Cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor Cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune Checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor Cells. Together, these data describe activation of the G2/M Cell Cycle Checkpoint in response to early and late CTL products as a mechanism of resistance to CTL killing, and provide pre-clinical rationale for the clinical combination of agents that inhibit Cell Cycle Checkpoints and activate anti-tumor immunity.
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WEE1 kinase inhibition reverses G2/M Cell Cycle Checkpoint activation to sensitize cancer Cells to immunotherapy
OncoImmunology, 2018Co-Authors: Ellen C Moore, Rose Berman, Paul E Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T AllenAbstract:Intrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M Cell Cycle Checkpoint results in tumor Cell Cycle pause and protection from granzyme B-induced Cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor Cells. Similarly, but at a later time point, Cell Cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor Cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune Checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor Cells. Together, these data describe activation of the G2/M Cell Cycle Checkpoint in response to early and late CTL products as a mechanism of resistance to CTL killing, and provide pre-clinical rationale for the clinical combination of agents that inhibit Cell Cycle Checkpoints and activate anti-tumor immunity.
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wee1 kinase inhibition reverses g2 m Cell Cycle Checkpoint activation to sensitize cancer Cells to immunotherapy
OncoImmunology, 2018Co-Authors: Ellen C Moore, Rose Berman, Paul E Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T AllenAbstract:ABSTRACTIntrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M Cell Cycle Checkpoint results in tumor Cell Cycle pause and protection from granzyme B-induced Cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor Cells. Similarly, but at a later time point, Cell Cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor Cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune Checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor Cells. Togeth...
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inhibition of wee1 kinase and Cell Cycle Checkpoint activation sensitizes head and neck cancers to natural killer Cell therapies
Journal for ImmunoTherapy of Cancer, 2018Co-Authors: Jay Friedman, Ellen C Moore, Clint T Allen, Megan Morisada, Michelle R Padget, James W Hodge, Jeffrey Schlom, Sofia R GameiroAbstract:Natural killer (NK) Cells recognize and lyse target tumor Cells in an MHC-unrestricted fashion and complement antigen- and MHC-restricted killing by T-lymphocytes. NK Cells and T-lymphocytes mediate early killing of targets through a common granzyme B-dependent mechanism. Tumor Cell resistance to granzyme B and how this alters NK Cell killing is not clearly defined. Tumor Cell sensitivity to cultured murine KIL and human high affinity NK (haNK) Cells in the presence or absence of AZD1775, a small molecule inhibitor of WEE1 kinase, was assessed via real time impedance analysis. Mechanisms of enhanced sensitivity to NK lysis were determined and in vivo validation via adoptive transfer of KIL Cells into syngeneic mice was performed. Cultured murine KIL Cells lyse murine oral cancer 2 (MOC2) Cell targets more efficiently than freshly isolated peripheral murine NK Cells. MOC2 sensitivity to granzyme B-dependent KIL Cell lysis was enhanced by inhibition of WEE1 kinase, reversing G2/M Cell Cycle Checkpoint activation and resulting in enhanced DNA damage and apoptosis. Treatment of MOC2 tumor-bearing wild-type C57BL/6 mice with AZD1775 and adoptively transferred KIL Cells resulted in enhanced tumor growth control and survival over controls or either treatment alone. Validating these findings in human models, WEE1 kinase inhibition sensitized two human head and neck cancer Cell lines to direct lysis by haNK Cells. Further, WEE1 kinase inhibition sensitized these Cell lines to antibody-dependent Cell-mediated cytotoxicity when combined with the anti-PD-L1 IgG1 mAb Avelumab. Tumor Cell resistance to granzyme B-induced Cell death can be reversed through inhibition of WEE1 kinase as AZD1775 sensitized both murine and human head and neck cancer Cells to NK lysis. These data provide the pre-clinical rationale for the combination of small molecules that reverse Cell Cycle Checkpoint activation and NK Cellular therapies.
Jay Friedman - One of the best experts on this subject based on the ideXlab platform.
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enhancing direct cytotoxicity and response to immune Checkpoint blockade following ionizing radiation with wee1 kinase inhibition
OncoImmunology, 2019Co-Authors: Priya Patel, Paul E Clavijo, Carter Van Waes, Jay Friedman, Yvette Robbins, Christopher Silvin, John A Cook, James B Mitchell, Clint T AllenAbstract:ABSTRACTTumor Cells activate the G2/M Cell Cycle Checkpoint in response to ionizing radiation (IR) and effector immune Cell-derived granzyme B to facilitate repair and survival. Wee1 kinase inhibit...
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wee1 kinase inhibition reverses g2 m Cell Cycle Checkpoint activation to sensitize cancer Cells to immunotherapy
OncoImmunology, 2018Co-Authors: Ellen C Moore, Rose Berman, Paul E Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T AllenAbstract:Intrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M Cell Cycle Checkpoint results in tumor Cell Cycle pause and protection from granzyme B-induced Cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor Cells. Similarly, but at a later time point, Cell Cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor Cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune Checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor Cells. Together, these data describe activation of the G2/M Cell Cycle Checkpoint in response to early and late CTL products as a mechanism of resistance to CTL killing, and provide pre-clinical rationale for the clinical combination of agents that inhibit Cell Cycle Checkpoints and activate anti-tumor immunity.
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WEE1 kinase inhibition reverses G2/M Cell Cycle Checkpoint activation to sensitize cancer Cells to immunotherapy
OncoImmunology, 2018Co-Authors: Ellen C Moore, Rose Berman, Paul E Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T AllenAbstract:Intrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M Cell Cycle Checkpoint results in tumor Cell Cycle pause and protection from granzyme B-induced Cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor Cells. Similarly, but at a later time point, Cell Cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor Cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune Checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor Cells. Together, these data describe activation of the G2/M Cell Cycle Checkpoint in response to early and late CTL products as a mechanism of resistance to CTL killing, and provide pre-clinical rationale for the clinical combination of agents that inhibit Cell Cycle Checkpoints and activate anti-tumor immunity.
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wee1 kinase inhibition reverses g2 m Cell Cycle Checkpoint activation to sensitize cancer Cells to immunotherapy
OncoImmunology, 2018Co-Authors: Ellen C Moore, Rose Berman, Paul E Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T AllenAbstract:ABSTRACTIntrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M Cell Cycle Checkpoint results in tumor Cell Cycle pause and protection from granzyme B-induced Cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor Cells. Similarly, but at a later time point, Cell Cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor Cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune Checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor Cells. Togeth...
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inhibition of wee1 kinase and Cell Cycle Checkpoint activation sensitizes head and neck cancers to natural killer Cell therapies
Journal for ImmunoTherapy of Cancer, 2018Co-Authors: Jay Friedman, Ellen C Moore, Clint T Allen, Megan Morisada, Michelle R Padget, James W Hodge, Jeffrey Schlom, Sofia R GameiroAbstract:Natural killer (NK) Cells recognize and lyse target tumor Cells in an MHC-unrestricted fashion and complement antigen- and MHC-restricted killing by T-lymphocytes. NK Cells and T-lymphocytes mediate early killing of targets through a common granzyme B-dependent mechanism. Tumor Cell resistance to granzyme B and how this alters NK Cell killing is not clearly defined. Tumor Cell sensitivity to cultured murine KIL and human high affinity NK (haNK) Cells in the presence or absence of AZD1775, a small molecule inhibitor of WEE1 kinase, was assessed via real time impedance analysis. Mechanisms of enhanced sensitivity to NK lysis were determined and in vivo validation via adoptive transfer of KIL Cells into syngeneic mice was performed. Cultured murine KIL Cells lyse murine oral cancer 2 (MOC2) Cell targets more efficiently than freshly isolated peripheral murine NK Cells. MOC2 sensitivity to granzyme B-dependent KIL Cell lysis was enhanced by inhibition of WEE1 kinase, reversing G2/M Cell Cycle Checkpoint activation and resulting in enhanced DNA damage and apoptosis. Treatment of MOC2 tumor-bearing wild-type C57BL/6 mice with AZD1775 and adoptively transferred KIL Cells resulted in enhanced tumor growth control and survival over controls or either treatment alone. Validating these findings in human models, WEE1 kinase inhibition sensitized two human head and neck cancer Cell lines to direct lysis by haNK Cells. Further, WEE1 kinase inhibition sensitized these Cell lines to antibody-dependent Cell-mediated cytotoxicity when combined with the anti-PD-L1 IgG1 mAb Avelumab. Tumor Cell resistance to granzyme B-induced Cell death can be reversed through inhibition of WEE1 kinase as AZD1775 sensitized both murine and human head and neck cancer Cells to NK lysis. These data provide the pre-clinical rationale for the combination of small molecules that reverse Cell Cycle Checkpoint activation and NK Cellular therapies.
Chuxia Deng - One of the best experts on this subject based on the ideXlab platform.
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wee1 inhibition targets Cell Cycle Checkpoints for triple negative breast cancers to overcome cisplatin resistance
Scientific Reports, 2017Co-Authors: Hongping Zheng, Chuxia Deng, Xiaoling Xu, Fangyuan Shao, Scots MartinAbstract:Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) Cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer Cells to cisplatin-induced lethality, because it not only impairs DNA replication Checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M Cell Cycle Checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M Cell Cycle Checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance.
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brca1 Cell Cycle Checkpoint genetic instability dna damage response and cancer evolution
Nucleic Acids Research, 2006Co-Authors: Chuxia DengAbstract:Germline mutations of the breast cancer associated gene 1 (BRCA1) predispose women to breast and ovarian cancers. BRCA1 is a large protein with multiple functional domains and interacts with numerous proteins that are involved in many important biological processes/pathways. Mounting evidence indicates that BRCA1 is involved in all phases of the Cell Cycle and regulates orderly events during Cell Cycle progression. BRCA1 deficiency, consequently causes abnormalities in the S-phase Checkpoint, the G2/M Checkpoint, the spindle Checkpoint and centrosome duplication. The genetic instability caused by BRCA1 deficiency, however, also triggers Cellular responses to DNA damage that blocks Cell proliferation and induces apoptosis. Thus BRCA1 mutant Cells cannot develop further into full-grown tumors unless this Cellular defense is broken. Functional analysis of BRCA1 in Cell Cycle Checkpoints, genome integrity, DNA damage response (DDR) and tumor evolution should benefit our understanding of the mechanisms underlying BRCA1 associated tumorigenesis, as well as the development of therapeutic approaches for this lethal disease.
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centrosome amplification and a defective g2 m Cell Cycle Checkpoint induce genetic instability in brca1 exon 11 isoform deficient Cells
Molecular Cell, 1999Co-Authors: Xiaoling Xu, Zoe Weaver, Steven P Linke, Cuiling Li, Jessica Gotay, Xin Wei Wang, Curtis C Harris, Thomas Ried, Chuxia DengAbstract:Abstract Germline mutations of the Brca1 tumor suppressor gene predispose women to breast and ovarian cancers. To study mechanisms underlying BRCA1-related tumorigenesis, we derived mouse embryonic fibroblast Cells carrying a targeted deletion of exon 11 of the Brca1 gene. We show that the mutant Cells maintain an intact G 1 –S Cell Cycle Checkpoint and proliferate poorly. However, a defective G 2 –M Checkpoint in these Cells is accompanied by extensive chromosomal abnormalities. Mutant fibroblasts contain multiple, functional centrosomes, which lead to unequal chromosome segregation, abnormal nuclear division, and aneuploidy. These data uncover an essential role of BRCA1 in maintaining genetic stability through the regulation of centrosome duplication and the G 2 –M Checkpoint and provide a molecular basis for the role of BRCA1 in tumorigenesis.
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atm selectively regulates distinct p53 dependent Cell Cycle Checkpoint and apoptotic pathways
Nature Genetics, 1997Co-Authors: Carrolee Barlow, Kevin D Brown, Chuxia Deng, Danilo A Tagle, Anthony WynshawborisAbstract:Atm is part of a pathway that responds to DMA damage from ionizing radiation (IR). This pathway involves p53 as Atm-deficient Cell lines and mice are defective in p53 induction after IR1–5. p53 is a multi-functional protein that simultaneously regulates distinct downstream pathways controlling Cell-Cycle progression and apoptosis6,7. However, the mechanisms by which p53 differentially activates downstream pathways are unknown. To determine the relationship between Atm and p53, we examined Cell-Cycle and apoptotic responses in Atm-, p53- (ref. 8) and p27-deficient9 mice after IR in the whole animal. As expected, p53 protein levels were not induced by IR in thymus of Atm-deiicient mice. IR-induced Cell-Cycle Checkpoint function was also defective, and induction of p21 was attenuated in thymus from >U/7?-deficient mice. However, IR-induced apoptosis and Bax induction were completely normal; both of which are mediated by p53. IR-induced thymic apoptosis was suppressed in Atm/p53 double-mutant mice but not in Atm/p21 double mutants, demonstrating p53 dependence and Atm independence. Thus, Atm deficiency results in lack of p53 induction by IR, but only selective disruption of p53-dependent functions. Our results support a model in which upstream effectors such as Atm selectively activate p53 to regulate specific downstream pathways, providing a mechanism for controlling distinct Cell-Cycle and apoptotic responses.
Ellen C Moore - One of the best experts on this subject based on the ideXlab platform.
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wee1 kinase inhibition reverses g2 m Cell Cycle Checkpoint activation to sensitize cancer Cells to immunotherapy
OncoImmunology, 2018Co-Authors: Ellen C Moore, Rose Berman, Paul E Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T AllenAbstract:Intrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M Cell Cycle Checkpoint results in tumor Cell Cycle pause and protection from granzyme B-induced Cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor Cells. Similarly, but at a later time point, Cell Cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor Cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune Checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor Cells. Together, these data describe activation of the G2/M Cell Cycle Checkpoint in response to early and late CTL products as a mechanism of resistance to CTL killing, and provide pre-clinical rationale for the clinical combination of agents that inhibit Cell Cycle Checkpoints and activate anti-tumor immunity.
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WEE1 kinase inhibition reverses G2/M Cell Cycle Checkpoint activation to sensitize cancer Cells to immunotherapy
OncoImmunology, 2018Co-Authors: Ellen C Moore, Rose Berman, Paul E Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T AllenAbstract:Intrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M Cell Cycle Checkpoint results in tumor Cell Cycle pause and protection from granzyme B-induced Cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor Cells. Similarly, but at a later time point, Cell Cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor Cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune Checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor Cells. Together, these data describe activation of the G2/M Cell Cycle Checkpoint in response to early and late CTL products as a mechanism of resistance to CTL killing, and provide pre-clinical rationale for the clinical combination of agents that inhibit Cell Cycle Checkpoints and activate anti-tumor immunity.
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wee1 kinase inhibition reverses g2 m Cell Cycle Checkpoint activation to sensitize cancer Cells to immunotherapy
OncoImmunology, 2018Co-Authors: Ellen C Moore, Rose Berman, Paul E Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T AllenAbstract:ABSTRACTIntrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M Cell Cycle Checkpoint results in tumor Cell Cycle pause and protection from granzyme B-induced Cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor Cells. Similarly, but at a later time point, Cell Cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor Cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune Checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor Cells. Togeth...
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inhibition of wee1 kinase and Cell Cycle Checkpoint activation sensitizes head and neck cancers to natural killer Cell therapies
Journal for ImmunoTherapy of Cancer, 2018Co-Authors: Jay Friedman, Ellen C Moore, Clint T Allen, Megan Morisada, Michelle R Padget, James W Hodge, Jeffrey Schlom, Sofia R GameiroAbstract:Natural killer (NK) Cells recognize and lyse target tumor Cells in an MHC-unrestricted fashion and complement antigen- and MHC-restricted killing by T-lymphocytes. NK Cells and T-lymphocytes mediate early killing of targets through a common granzyme B-dependent mechanism. Tumor Cell resistance to granzyme B and how this alters NK Cell killing is not clearly defined. Tumor Cell sensitivity to cultured murine KIL and human high affinity NK (haNK) Cells in the presence or absence of AZD1775, a small molecule inhibitor of WEE1 kinase, was assessed via real time impedance analysis. Mechanisms of enhanced sensitivity to NK lysis were determined and in vivo validation via adoptive transfer of KIL Cells into syngeneic mice was performed. Cultured murine KIL Cells lyse murine oral cancer 2 (MOC2) Cell targets more efficiently than freshly isolated peripheral murine NK Cells. MOC2 sensitivity to granzyme B-dependent KIL Cell lysis was enhanced by inhibition of WEE1 kinase, reversing G2/M Cell Cycle Checkpoint activation and resulting in enhanced DNA damage and apoptosis. Treatment of MOC2 tumor-bearing wild-type C57BL/6 mice with AZD1775 and adoptively transferred KIL Cells resulted in enhanced tumor growth control and survival over controls or either treatment alone. Validating these findings in human models, WEE1 kinase inhibition sensitized two human head and neck cancer Cell lines to direct lysis by haNK Cells. Further, WEE1 kinase inhibition sensitized these Cell lines to antibody-dependent Cell-mediated cytotoxicity when combined with the anti-PD-L1 IgG1 mAb Avelumab. Tumor Cell resistance to granzyme B-induced Cell death can be reversed through inhibition of WEE1 kinase as AZD1775 sensitized both murine and human head and neck cancer Cells to NK lysis. These data provide the pre-clinical rationale for the combination of small molecules that reverse Cell Cycle Checkpoint activation and NK Cellular therapies.
Carter Van Waes - One of the best experts on this subject based on the ideXlab platform.
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enhancing direct cytotoxicity and response to immune Checkpoint blockade following ionizing radiation with wee1 kinase inhibition
OncoImmunology, 2019Co-Authors: Priya Patel, Paul E Clavijo, Carter Van Waes, Jay Friedman, Yvette Robbins, Christopher Silvin, John A Cook, James B Mitchell, Clint T AllenAbstract:ABSTRACTTumor Cells activate the G2/M Cell Cycle Checkpoint in response to ionizing radiation (IR) and effector immune Cell-derived granzyme B to facilitate repair and survival. Wee1 kinase inhibit...
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wee1 kinase inhibition reverses g2 m Cell Cycle Checkpoint activation to sensitize cancer Cells to immunotherapy
OncoImmunology, 2018Co-Authors: Ellen C Moore, Rose Berman, Paul E Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T AllenAbstract:Intrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M Cell Cycle Checkpoint results in tumor Cell Cycle pause and protection from granzyme B-induced Cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor Cells. Similarly, but at a later time point, Cell Cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor Cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune Checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor Cells. Together, these data describe activation of the G2/M Cell Cycle Checkpoint in response to early and late CTL products as a mechanism of resistance to CTL killing, and provide pre-clinical rationale for the clinical combination of agents that inhibit Cell Cycle Checkpoints and activate anti-tumor immunity.
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WEE1 kinase inhibition reverses G2/M Cell Cycle Checkpoint activation to sensitize cancer Cells to immunotherapy
OncoImmunology, 2018Co-Authors: Ellen C Moore, Rose Berman, Paul E Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T AllenAbstract:Intrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M Cell Cycle Checkpoint results in tumor Cell Cycle pause and protection from granzyme B-induced Cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor Cells. Similarly, but at a later time point, Cell Cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor Cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune Checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor Cells. Together, these data describe activation of the G2/M Cell Cycle Checkpoint in response to early and late CTL products as a mechanism of resistance to CTL killing, and provide pre-clinical rationale for the clinical combination of agents that inhibit Cell Cycle Checkpoints and activate anti-tumor immunity.
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wee1 kinase inhibition reverses g2 m Cell Cycle Checkpoint activation to sensitize cancer Cells to immunotherapy
OncoImmunology, 2018Co-Authors: Ellen C Moore, Rose Berman, Paul E Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T AllenAbstract:ABSTRACTIntrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M Cell Cycle Checkpoint results in tumor Cell Cycle pause and protection from granzyme B-induced Cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor Cells. Similarly, but at a later time point, Cell Cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor Cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune Checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor Cells. Togeth...