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Article ; Online: Combined inhibition of PIM and CDK4/6 suppresses both mTOR signaling and Rb phosphorylation and potentiates PI3K inhibition in cancer cells.

Litchfield, Lacey M / Boehnke, Karsten / Brahmachary, Manisha / Mur, Cecilia / Bi, Chen / Stephens, Jennifer R / Sauder, J Michael / Gutiérrez, Sonia M / McNulty, Ann M / Ye, Xiang S / Wu, Wenjuan / Lallena, María José / Gong, Xueqian / Merzoug, Farhana F / Jansen, Valerie M / Buchanan, Sean G

Oncotarget

2020 Volume 11, Issue 17, Page(s) 1478–1492

Abstract: Aberrant activation of mitogenic signaling pathways in cancer promotes growth and proliferation of cells by activating mTOR and S6 phosphorylation, and D-cyclin kinases and Rb phosphorylation, respectively. Correspondingly, inhibition of phosphorylation ... ...

Abstract	Aberrant activation of mitogenic signaling pathways in cancer promotes growth and proliferation of cells by activating mTOR and S6 phosphorylation, and D-cyclin kinases and Rb phosphorylation, respectively. Correspondingly, inhibition of phosphorylation of both Rb and S6 is required for robust anti-tumor efficacy of drugs that inhibit cell signaling. The best-established mechanism of mTOR activation in cancer is via PI3K/Akt signaling, but mTOR activity can also be stimulated by CDK4 and PIM kinases. In this study, we show that the CDK4/6 inhibitor abemaciclib inhibits PIM kinase and S6 phosphorylation in cancer cells and concurrent inhibition of PIM, CDK4, and CDK6 suppresses both S6 and Rb phosphorylation.
Language	English
Publishing date	2020-04-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.27539
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A pan-cancer transcriptome analysis identifies replication fork and innate immunity genes as modifiers of response to the CHK1 inhibitor prexasertib.

Oncotarget

2020 Volume 11, Issue 3, Page(s) 216–236

Abstract: The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for ... ...

Abstract	The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and
Language	English
Publishing date	2020-01-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.27400
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade.

Cell reports

2018 Volume 22, Issue 11, Page(s) 2978–2994

Abstract: Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the ... ...

Abstract	Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control. In vitro, treatment with abemaciclib resulted in increased activation of human T cells and upregulated expression of antigen presentation genes in MCF-7 breast cancer cells. These data collectively support the clinical investigation of the combination of abemaciclib with agents such as anti-PD-L1 that modulate T cell anti-tumor immunity.
MeSH term(s)	Aminopyridines/pharmacology ; Aminopyridines/therapeutic use ; Benzimidazoles/pharmacology ; Benzimidazoles/therapeutic use ; Cyclin-Dependent Kinase Inhibitor p15/pharmacology ; Cyclin-Dependent Kinase Inhibitor p15/therapeutic use ; Cyclin-Dependent Kinase Inhibitor p18/pharmacology ; Cyclin-Dependent Kinase Inhibitor p18/therapeutic use ; Humans ; Programmed Cell Death 1 Receptor/metabolism ; Tumor Microenvironment
Chemical Substances	5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-yl)-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)pyrimidin-2-yl)amine ; Aminopyridines ; Benzimidazoles ; Cyclin-Dependent Kinase Inhibitor p15 ; Cyclin-Dependent Kinase Inhibitor p18 ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2018-03-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2018.02.053
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Article ; Online: A Novel Eg5 Inhibitor (LY2523355) Causes Mitotic Arrest and Apoptosis in Cancer Cells and Shows Potent Antitumor Activity in Xenograft Tumor Models.

Ye, Xiang S / Fan, Li / Van Horn, Robert D / Nakai, Ryuichiro / Ohta, Yoshihisa / Akinaga, Shiro / Murakata, Chikara / Yamashita, Yoshinori / Yin, Tinggui / Credille, Kelly M / Donoho, Gregory P / Merzoug, Farhana F / Li, Heng / Aggarwal, Amit / Blanchard, Kerry / Westin, Eric H

Molecular cancer therapeutics

2015 Volume 14, Issue 11, Page(s) 2463–2472

Abstract: Intervention of cancer cell mitosis by antitubulin drugs is among the most effective cancer chemotherapies. However, antitubulin drugs have dose-limiting side effects due to important functions of microtubules in resting normal cells and are often ... ...

Abstract	Intervention of cancer cell mitosis by antitubulin drugs is among the most effective cancer chemotherapies. However, antitubulin drugs have dose-limiting side effects due to important functions of microtubules in resting normal cells and are often rendered ineffective by rapid emergence of resistance. Antimitotic agents with different mechanisms of action and improved safety profiles are needed as new treatment options. Mitosis-specific kinesin Eg5 represents an attractive anticancer target for discovering such new antimitotic agents, because Eg5 is essential only in mitotic progression and has no roles in resting, nondividing cells. Here, we show that a novel selective Eg5 inhibitor, LY2523355, has broad target-mediated anticancer activity in vitro and in vivo. LY2523355 arrests cancer cells at mitosis and causes rapid cell death that requires sustained spindle-assembly checkpoint (SAC) activation with a required threshold concentration. In vivo efficacy of LY2523355 is highly dose/schedule-dependent, achieving complete remission in a number of xenograft tumor models, including patient-derived xenograft (PDX) tumor models. We further establish that histone-H3 phosphorylation of tumor and proliferating skin cells is a promising pharmacodynamic biomarker for in vivo anticancer activity of LY2523355.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; HCT116 Cells ; HT29 Cells ; HeLa Cells ; Humans ; Immunoblotting ; Kinesin/antagonists & inhibitors ; Kinesin/metabolism ; Mice, Nude ; Mitosis/drug effects ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Sulfonamides/pharmacology ; Thiadiazoles/pharmacology ; Time Factors ; Treatment Outcome ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	Apoptosis Regulatory Proteins ; KIF11 protein, human ; Sulfonamides ; Thiadiazoles ; litronesib (6611F8KYCV) ; Kinesin (EC 3.6.4.4)
Language	English
Publishing date	2015-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-15-0241
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Article ; Online: Preclinical analyses and phase I evaluation of LY2603618 administered in combination with pemetrexed and cisplatin in patients with advanced cancer.

Calvo, Emiliano / Chen, Victor J / Marshall, Mark / Ohnmacht, Ute / Hynes, Scott M / Kumm, Elizabeth / Diaz, H Bruce / Barnard, Darlene / Merzoug, Farhana F / Huber, Lysiane / Kays, Lisa / Iversen, Philip / Calles, Antonio / Voss, Beatrice / Lin, Aimee Bence / Dickgreber, Nicolas / Wehler, Thomas / Sebastian, Martin

Investigational new drugs

2014 Volume 32, Issue 5, Page(s) 955–968

Abstract: LY2603618 is an inhibitor of checkpoint kinase 1 (CHK1), an important regulator of the DNA damage checkpoints. Preclinical experiments analyzed NCI-H2122 and NCI-H441 NSCLC cell lines and in vitro/in vivo models treated with pemetrexed and LY2603618 to ... ...

Abstract	LY2603618 is an inhibitor of checkpoint kinase 1 (CHK1), an important regulator of the DNA damage checkpoints. Preclinical experiments analyzed NCI-H2122 and NCI-H441 NSCLC cell lines and in vitro/in vivo models treated with pemetrexed and LY2603618 to provide rationale for evaluating this combination in a clinical setting. Combination treatment of LY2603618 with pemetrexed arrested DNA synthesis following initiation of S-phase in cells. Experiments with tumor-bearing mice administered the combination of LY2603618 and pemetrexed demonstrated a significant increase of growth inhibition of NCI-H2122 (H2122) and NCI-H441 (H441) xenograft tumors. These data informed the clinical assessment of LY2603618 in a seamless phase I/II study, which administered pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) and escalating doses of LY2603618: 130-275 mg. Patients were assessed for safety, toxicity, and pharmacokinetics. In phase I, 14 patients were enrolled, and the most frequently reported adverse events included fatigue, nausea, pyrexia, neutropenia, and vomiting. No DLTs were reported at the tested doses. The systemic exposure of LY2603618 increased in a dose-dependent manner. Pharmacokinetic parameters that correlate with the maximal pharmacodynamic effect in nonclinical xenograft models were achieved at doses ≥240 mg. The pharmacokinetics of LY2603618, pemetrexed, and cisplatin were not altered when used in combination. Two patients achieved a confirmed partial response (both non-small cell lung cancer), and 8 patients had stable disease. LY2603618 administered in combination with pemetrexed and cisplatin demonstrated an acceptable safety profile. The recommended phase II dose of LY2603618 was 275 mg.
MeSH term(s)	Adult ; Aged ; Animals ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/blood ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Cell Line, Tumor ; Cisplatin/administration & dosage ; Cisplatin/adverse effects ; Cisplatin/blood ; Cisplatin/pharmacokinetics ; DNA/metabolism ; Female ; Glutamates/administration & dosage ; Glutamates/adverse effects ; Glutamates/blood ; Glutamates/pharmacokinetics ; Guanine/administration & dosage ; Guanine/adverse effects ; Guanine/analogs & derivatives ; Guanine/blood ; Guanine/pharmacokinetics ; Humans ; Male ; Mice, Nude ; Middle Aged ; Neoplasms/blood ; Neoplasms/drug therapy ; Neoplasms/pathology ; Pemetrexed ; Phenylurea Compounds/administration & dosage ; Phenylurea Compounds/adverse effects ; Phenylurea Compounds/blood ; Phenylurea Compounds/pharmacokinetics ; Pyrazines/administration & dosage ; Pyrazines/adverse effects ; Pyrazines/blood ; Pyrazines/pharmacokinetics ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	Glutamates ; LY2603618 ; Phenylurea Compounds ; Pyrazines ; Pemetrexed (04Q9AIZ7NO) ; Guanine (5Z93L87A1R) ; DNA (9007-49-2) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2014-06-20
Publishing country	United States
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
ZDB-ID	604895-x
ISSN	1573-0646 ; 0167-6997
ISSN (online)	1573-0646
ISSN	0167-6997
DOI	10.1007/s10637-014-0114-5
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Zs.A 1823: Show issues

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Article ; Online: Genomic Aberrations that Activate D-type Cyclins Are Associated with Enhanced Sensitivity to the CDK4 and CDK6 Inhibitor Abemaciclib.

Gong, Xueqian / Litchfield, Lacey M / Webster, Yue / Chio, Li-Chun / Wong, Swee Seong / Stewart, Trent R / Dowless, Michele / Dempsey, Jack / Zeng, Yi / Torres, Raquel / Boehnke, Karsten / Mur, Cecilia / Marugán, Carlos / Baquero, Carmen / Yu, Chunping / Bray, Steven M / Wulur, Isabella H / Bi, Chen / Chu, Shaoyou /

Qian, Hui-Rong / Iversen, Philip W / Merzoug, Farhana F / Ye, Xiang S / Reinhard, Christoph / De Dios, Alfonso / Du, Jian / Caldwell, Charles W / Lallena, María José / Beckmann, Richard P / Buchanan, Sean G

Cancer cell

2017 Volume 32, Issue 6, Page(s) 761–776.e6

Abstract: Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is ... ...

Abstract	Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3'UTR mutation associated with increased expression in endometrial cancer. The results suggest multiple additional classes of cancer that may benefit from CDK4/6-inhibiting drugs such as abemaciclib.
MeSH term(s)	Aminopyridines/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Benzimidazoles/pharmacology ; Cell Proliferation/drug effects ; Clinical Trials, Phase I as Topic ; Cyclin D/genetics ; Cyclin D/metabolism ; Cyclin-Dependent Kinase 4/antagonists & inhibitors ; Cyclin-Dependent Kinase 6/antagonists & inhibitors ; Female ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Xenograft Model Antitumor Assays
Chemical Substances	5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-yl)-(5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)pyrimidin-2-yl)amine ; Aminopyridines ; Antineoplastic Agents ; Benzimidazoles ; Cyclin D ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 6 (EC 2.7.11.22)
Language	English
Publishing date	2017-12-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2017.11.006
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Zs.A 5650: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 104: Show issues

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Article ; Online: Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the

Gong, Xueqian / Du, Jian / Parsons, Stephen H / Merzoug, Farhana F / Webster, Yue / Iversen, Philip W / Chio, Li-Chun / Van Horn, Robert D / Lin, Xi / Blosser, Wayne / Han, Bomie / Jin, Shaoling / Yao, Sufang / Bian, Huimin / Ficklin, Chris / Fan, Li / Kapoor, Avnish / Antonysamy, Stephen / Mc Nulty, Ann M /

Cancer discovery

2018 Volume 9, Issue 2, Page(s) 248–263

Abstract: Loss-of-function mutations in the retinoblastoma ... ...

Abstract	Loss-of-function mutations in the retinoblastoma gene
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Apoptosis ; Aurora Kinase A/antagonists & inhibitors ; Aurora Kinase A/genetics ; Aurora Kinase A/metabolism ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation ; Enzyme Inhibitors/pharmacology ; Female ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; M Phase Cell Cycle Checkpoints/drug effects ; Mice ; Mice, Nude ; Retinoblastoma Binding Proteins/genetics ; Retinoblastoma Binding Proteins/metabolism ; Signal Transduction ; Small Cell Lung Carcinoma/drug therapy ; Small Cell Lung Carcinoma/metabolism ; Small Cell Lung Carcinoma/pathology ; Tumor Cells, Cultured ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; RB1 protein, human ; Retinoblastoma Binding Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; AURKA protein, human (EC 2.7.11.1) ; Aurora Kinase A (EC 2.7.11.1)
Language	English
Publishing date	2018-10-29
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-18-0469
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Article ; Online: Combined inhibition of PIM and CDK4/6 suppresses both mTOR signaling and Rb phosphorylation and potentiates PI3K inhibition in cancer cells.

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Article ; Online: A pan-cancer transcriptome analysis identifies replication fork and innate immunity genes as modifiers of response to the CHK1 inhibitor prexasertib.

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Article ; Online: The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade.

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Article ; Online: A Novel Eg5 Inhibitor (LY2523355) Causes Mitotic Arrest and Apoptosis in Cancer Cells and Shows Potent Antitumor Activity in Xenograft Tumor Models.

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Article ; Online: Preclinical analyses and phase I evaluation of LY2603618 administered in combination with pemetrexed and cisplatin in patients with advanced cancer.

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Article ; Online: Genomic Aberrations that Activate D-type Cyclins Are Associated with Enhanced Sensitivity to the CDK4 and CDK6 Inhibitor Abemaciclib.

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Article ; Online: Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the

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