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Article ; Online: BET inhibition targets ABC-DLBCL constitutive B-cell receptor signaling through PAX5.

Oien, Derek B / Sharma, Samanta / Hattersley, Maureen M / DuPont, Michelle / Criscione, Steven W / Prickett, Laura / Goeppert, Anne U / Drew, Lisa / Yao, Yi / Zhang, Jingwen / Chan, Ho Man

Blood advances

2023 Volume 7, Issue 17, Page(s) 5108–5121

Abstract: B-cell receptor (BCR) signaling is essential for the diffuse large B-cell lymphoma (DLBCL) subtype that originates from activated B-cells (ABCs). ABC-DLBCL cells are sensitive to Bruton tyrosine kinase intervention. However, patients with relapsed or ... ...

Abstract	B-cell receptor (BCR) signaling is essential for the diffuse large B-cell lymphoma (DLBCL) subtype that originates from activated B-cells (ABCs). ABC-DLBCL cells are sensitive to Bruton tyrosine kinase intervention. However, patients with relapsed or refractory ABC-DLBCL had overall response rates from 33% to 37% for Bruton tyrosine kinase inhibitors, suggesting the evaluation of combination-based treatment for improved efficacy. We investigated the efficacy and mechanism of the bromodomain and extraterminal motif (BET) inhibitor AZD5153 combined with the Bruton tyrosine kinase inhibitor acalabrutinib in ABC-DLBCL preclinical models. AZD5153 is a bivalent BET inhibitor that simultaneously engages the 2 bromodomains of BRD4. Adding AZD5153 to acalabrutinib demonstrated combination benefits in ABC-DLBCL cell line and patient-derived xenograft models. Differential expression analyses revealed PAX5 transcriptional activity as a novel downstream effector of this drug combination. PAX5 is a transcription factor for BCR signaling genes and may be critical for perpetually active BCR signaling in ABC-DLBCL. Our analyses further indicated significant alterations in BCR, RELB/alternative NF-κB, and toll-like receptor/interferon signaling. Validation of these results mapped a positive-feedback signaling loop regulated by PAX5. We demonstrated that AZD5153 decreased PAX5 expression, whereas acalabrutinib disruption of BCR signaling inhibited PAX5 activation. Furthermore, several interferon levels were decreased by AZD5153 and acalabrutinib in tumors. Adding interferon-beta1 (IFNβ1) to cells treated with acalabrutinib partially rescued PAX5 activation. Our results demonstrate that AZD5153 enhances the efficacy of acalabrutinib through PAX5 and BCR mechanisms that are critical for ABC-DLBCL.
MeSH term(s)	Humans ; Nuclear Proteins/metabolism ; Transcription Factors/metabolism ; Receptors, Antigen, B-Cell/metabolism ; Interferons ; Cell Cycle Proteins ; PAX5 Transcription Factor/genetics
Chemical Substances	acalabrutinib (I42748ELQW) ; Nuclear Proteins ; Transcription Factors ; Receptors, Antigen, B-Cell ; Interferons (9008-11-1) ; BRD4 protein, human ; Cell Cycle Proteins ; PAX5 protein, human ; PAX5 Transcription Factor
Language	English
Publishing date	2023-05-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2022009257
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Article ; Online: A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models.

White, Michael J / Cheatham, Letitia / Wen, Shenghua / Scarfe, Graeme / Cidado, Justin / Reimer, Corinne / Hariparsad, Niresh / Jones, Rhys D O / Drew, Lisa / McGinnity, Dermot F / Vasalou, Christina

The AAPS journal

2023 Volume 25, Issue 4, Page(s) 66

Abstract: Capturing human equivalent drug exposures preclinically is a key challenge in the translational process. Motivated by the need to recapitulate the pharmacokinetic (PK) profile of the clinical stage Mcl-1 inhibitor AZD5991 in mice, we describe the ... ...

Abstract	Capturing human equivalent drug exposures preclinically is a key challenge in the translational process. Motivated by the need to recapitulate the pharmacokinetic (PK) profile of the clinical stage Mcl-1 inhibitor AZD5991 in mice, we describe the methodology used to develop a refined mathematical model relating clinically relevant concentration profiles to efficacy. Administration routes were explored to achieve target exposures matching the clinical exposure of AZD5991. Intravenous infusion using vascular access button (VAB) technology was found to best reproduce clinical target exposures of AZD5991 in mice. Exposure-efficacy relationships were evaluated, demonstrating that dissimilar PK profiles result in differences in target engagement and efficacy outcomes. Thus, these data underscore the importance of accurately ascribing key PK metrics in the translational process to enable clinically meaningful predictions of efficacy.
MeSH term(s)	Humans ; Animals ; Mice ; Disease Models, Animal ; Macrocyclic Compounds ; Medical Oncology ; Technology
Chemical Substances	AZD5991 ; Macrocyclic Compounds
Language	English
Publishing date	2023-06-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1550-7416
ISSN (online)	1550-7416
DOI	10.1208/s12248-023-00836-z
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Article ; Online: Targeting MCL-1 dysregulates cell metabolism and leukemia-stroma interactions and resensitizes acute myeloid leukemia to BCL-2 inhibition.

Carter, Bing Z / Mak, Po Yee / Tao, Wenjing / Warmoes, Marc / Lorenzi, Philip L / Mak, Duncan / Ruvolo, Vivian / Tan, Lin / Cidado, Justin / Drew, Lisa / Andreeff, Michael

Haematologica

2022 Volume 107, Issue 1, Page(s) 58–76

Abstract: MCL-1 and BCL-2 are both frequently overexpressed in acute myeloid leukemia and critical for the survival of acute myeloid leukemia cells and acute myeloid leukemia stem cells. MCL-1 is a key factor in venetoclax resistance. Using genetic and ... ...

Abstract	MCL-1 and BCL-2 are both frequently overexpressed in acute myeloid leukemia and critical for the survival of acute myeloid leukemia cells and acute myeloid leukemia stem cells. MCL-1 is a key factor in venetoclax resistance. Using genetic and pharmacological approaches, we discovered that MCL-1 regulates leukemia cell bioenergetics and carbohydrate metabolisms, including the TCA cycle, glycolysis and pentose phosphate pathway and modulates cell adhesion proteins and leukemia-stromal interactions. Inhibition of MCL-1 sensitizes to BCL-2 inhibition in acute myeloid leukemia cells and acute myeloid leukemia stem/progenitor cells, including those with intrinsic and acquired resistance to venetoclax through cooperative release of pro-apoptotic BIM, BAX, and BAK from binding to anti-apoptotic BCL-2 proteins and inhibition of cell metabolism and key stromal microenvironmental mechanisms. The combined inhibition of MCL-1 by MCL-1 inhibitor AZD5991 or CDK9 inhibitor AZD4573 and BCL-2 by venetoclax greatly extended survival of mice bearing patient-derived xenografts established from an acute myeloid leukemia patient who acquired resistance to venetoclax/decitabine. These results demonstrate that co-targeting MCL-1 and BCL-2 improves the efficacy of and overcomes preexisting and acquired resistance to BCL-2 inhibition. Activation of metabolomic pathways and leukemia-stroma interactions are newly discovered functions of MCL-1 in acute myeloid leukemia, which are independent from canonical regulation of apoptosis by MCL-1. Our data provide new mechanisms of synergy and rationale for co-targeting MCL-1 and BCL-2 clinically in patients with acute myeloid leukemia and potentially other cancers.
MeSH term(s)	Animals ; Apoptosis ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Cell Line, Tumor ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Mice ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Proto-Oncogene Proteins c-bcl-2/genetics ; Sulfonamides/pharmacology
Chemical Substances	BCL2 protein, human ; Bridged Bicyclo Compounds, Heterocyclic ; MCL1 protein, human ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2 ; Sulfonamides ; venetoclax (N54AIC43PW)
Language	English
Publishing date	2022-01-01
Publishing country	Italy
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2020.260331
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Article ; Online: Targeting Bfl-1 via acute CDK9 inhibition overcomes intrinsic BH3-mimetic resistance in lymphomas.

Boiko, Scott / Proia, Theresa / San Martin, Maryann / Gregory, Gareth P / Wu, Michelle Min / Aryal, Neeraj / Hattersley, Maureen / Shao, Wenlin / Saeh, Jamal C / Fawell, Stephen E / Johnstone, Ricky W / Drew, Lisa / Cidado, Justin

Blood

2020 Volume 137, Issue 21, Page(s) 2947–2957

Abstract: BH3 mimetics like venetoclax target prosurvival Bcl-2 family proteins and are important therapeutics in the treatment of hematological malignancies. We demonstrate that endogenous Bfl-1 expression can render preclinical lymphoma tumor models insensitive ... ...

Abstract	BH3 mimetics like venetoclax target prosurvival Bcl-2 family proteins and are important therapeutics in the treatment of hematological malignancies. We demonstrate that endogenous Bfl-1 expression can render preclinical lymphoma tumor models insensitive to Mcl-1 and Bcl-2 inhibitors. However, suppression of Bfl-1 alone was insufficient to fully induce apoptosis in Bfl-1-expressing lymphomas, highlighting the need for targeting additional prosurvival proteins in this context. Importantly, we demonstrated that cyclin-dependent kinase 9 (CDK9) inhibitors rapidly downregulate both Bfl-1 and Mcl-1, inducing apoptosis in BH3-mimetic-resistant lymphoma cell lines in vitro and driving in vivo tumor regressions in diffuse large B-cell lymphoma patient-derived xenograft models expressing Bfl-1. These data underscore the need to clinically develop CDK9 inhibitors, like AZD4573, for the treatment of lymphomas using Bfl-1 as a selection biomarker.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Cell Line, Tumor ; Cyclin-Dependent Kinase 9/antagonists & inhibitors ; Cyclin-Dependent Kinase 9/physiology ; Cycloheximide/pharmacology ; Drug Resistance, Neoplasm/drug effects ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Leupeptins/pharmacology ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Macrocyclic Compounds/pharmacology ; Macrocyclic Compounds/therapeutic use ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Minor Histocompatibility Antigens/biosynthesis ; Minor Histocompatibility Antigens/genetics ; Molecular Targeted Therapy ; Myeloid Cell Leukemia Sequence 1 Protein/biosynthesis ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/genetics ; Peptide Fragments/antagonists & inhibitors ; Piperazines/pharmacology ; Proto-Oncogene Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Proto-Oncogene Proteins c-bcl-2/genetics ; Pyridines/pharmacology ; Sulfonamides/pharmacology ; Sulfonamides/therapeutic use ; Xenograft Model Antitumor Assays
Chemical Substances	AZD5991 ; Antineoplastic Agents ; BCL2-related protein A1 ; Bax protein (53-86) ; Bridged Bicyclo Compounds, Heterocyclic ; Leupeptins ; MCL1 protein, human ; Macrocyclic Compounds ; Minor Histocompatibility Antigens ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins ; Peptide Fragments ; Piperazines ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-bcl-2 ; Pyridines ; Sulfonamides ; Cycloheximide (98600C0908) ; CDK9 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 9 (EC 2.7.11.22) ; palbociclib (G9ZF61LE7G) ; venetoclax (N54AIC43PW) ; benzyloxycarbonylleucyl-leucyl-leucine aldehyde (RF1P63GW3K)
Language	English
Publishing date	2020-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2020008528
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Article ; Online: Multiscale Model Identifies Improved Schedule for Treatment of Acute Myeloid Leukemia In Vitro With the Mcl-1 Inhibitor AZD5991.

Goliaei, Ardeshir / Woods, Haley A / Tron, Adriana E / Belmonte, Matthew A / Secrist, J Paul / Ferguson, Douglas / Drew, Lisa / Fretland, Adrian J / Aldridge, Bree B / Gibbons, Francis D

CPT: pharmacometrics & systems pharmacology

2020 Volume 9, Issue 10, Page(s) 561–570

Abstract: Anticancer efficacy is driven not only by dose but also by frequency and duration of treatment. We describe a multiscale model combining cell cycle, cellular heterogeneity of B-cell lymphoma 2 family proteins, and pharmacology of AZD5991, a potent small- ... ...

Abstract	Anticancer efficacy is driven not only by dose but also by frequency and duration of treatment. We describe a multiscale model combining cell cycle, cellular heterogeneity of B-cell lymphoma 2 family proteins, and pharmacology of AZD5991, a potent small-molecule inhibitor of myeloid cell leukemia 1 (Mcl-1). The model was calibrated using in vitro viability data for the MV-4-11 acute myeloid leukemia cell line under continuous incubation for 72 hours at concentrations of 0.03-30 μM. Using a virtual screen, we identified two schedules as having significantly different predicted efficacy and showed experimentally that a "short" schedule (treating cells for 6 of 24 hours) is significantly better able to maintain the rate of cell kill during treatment than a "long" schedule (18 of 24 hours). This work suggests that resistance can be driven by heterogeneity in protein expression of Mcl-1 alone without requiring mutation or resistant subclones and demonstrates the utility of mathematical models in efficiently identifying regimens for experimental exploration.
MeSH term(s)	Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Cell Line, Tumor/drug effects ; Drug Administration Schedule ; Drug Resistance, Neoplasm ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/pathology ; Macrocyclic Compounds/administration & dosage ; Macrocyclic Compounds/pharmacology ; Macrocyclic Compounds/therapeutic use ; Mice ; Models, Animal ; Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors ; Xenograft Model Antitumor Assays/methods
Chemical Substances	AZD5991 ; Antineoplastic Agents ; MCL1 protein, human ; Macrocyclic Compounds ; Myeloid Cell Leukemia Sequence 1 Protein
Language	English
Publishing date	2020-09-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12552
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Article ; Online: Novel Arginase Inhibitor, AZD0011, Demonstrates Immune Cell Stimulation and Antitumor Efficacy with Diverse Combination Partners.

Doshi, Aatman S / Cantin, Susan / Hernandez, Marylens / Srinivasan, Srimathi / Tentarelli, Sharon / Griffin, Matthew / Wang, Yanjun / Pop-Damkov, Petar / Prickett, Laura B / Kankkonen, Cecilia / Shen, Minhui / Martin, Maryann San / Wu, Song / Castaldi, M Paola / Ghadially, Hormas / Varnes, Jeffrey / Gales, Sonya / Henry, David / Hoover, Clare /

Mele, Deanna A / Simpson, Iain / Gangl, Eric T / Mlynarski, Scott N / Finlay, M Raymond V / Drew, Lisa / Fawell, Stephen E / Shao, Wenlin / Schuller, Alwin G

Molecular cancer therapeutics

2023 Volume 22, Issue 5, Page(s) 630–645

Abstract: Antitumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment, including recruitment of arginase (ARG) expressing myeloid cells that deplete l-arginine essential for optimal T-cell and natural killer cell function. ... ...

Abstract	Antitumor immunity can be hampered by immunosuppressive mechanisms in the tumor microenvironment, including recruitment of arginase (ARG) expressing myeloid cells that deplete l-arginine essential for optimal T-cell and natural killer cell function. Hence, ARG inhibition can reverse immunosuppression enhancing antitumor immunity. We describe AZD0011, a novel peptidic boronic acid prodrug to deliver an orally available, highly potent, ARG inhibitor payload (AZD0011-PL). We demonstrate that AZD0011-PL is unable to permeate cells, suggesting that this compound will only inhibit extracellular ARG. In vivo, AZD0011 monotherapy leads to arginine increases, immune cell activation, and tumor growth inhibition in various syngeneic models. Antitumor responses increase when AZD0011 is combined with anti-PD-L1 treatment, correlating with increases in multiple tumor immune cell populations. We demonstrate a novel triple combination of AZD0011, anti-PD-L1, and anti-NKG2A, and combination benefits with type I IFN inducers, including polyI:C and radiotherapy. Our preclinical data demonstrate AZD0011's ability to reverse tumor immunosuppression and enhance immune stimulation and antitumor responses with diverse combination partners providing potential strategies to increase immuno-oncology therapies clinically.
MeSH term(s)	Humans ; Arginase ; Cell Line, Tumor ; T-Lymphocytes ; Immunosuppression Therapy ; Immune Tolerance ; Tumor Microenvironment
Chemical Substances	Arginase (EC 3.5.3.1)
Language	English
Publishing date	2023-03-11
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-22-0431
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Zs.A 5750: Show issues

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Article ; Online: An unusual presentation of metastatic adenocarcinoma of lung: a case report.

Ghumro, Muhammad Y / Drew, Lisa / Tariq, Syed M

Cases journal

2009 Volume 2, Page(s) 9401

Abstract: We report an unusual patient with primary adenocarcinoma of lung causing malignant pleural and pericardial effusions. The diagnosis was made only at autopsy as his staging computed tomography scan of chest was negative for an obvious mass lesion within ... ...

Abstract	We report an unusual patient with primary adenocarcinoma of lung causing malignant pleural and pericardial effusions. The diagnosis was made only at autopsy as his staging computed tomography scan of chest was negative for an obvious mass lesion within the lung or pleura. Prior to his death, his symptoms were erroneously managed as left ventricular failure and community-acquired pneumonia.
Language	English
Publishing date	2009-12-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2431132-7
ISSN	1757-1626 ; 1757-1626
ISSN (online)	1757-1626
ISSN	1757-1626
DOI	10.1186/1757-1626-2-9401
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Article ; Online: The CUL5 ubiquitin ligase complex mediates resistance to CDK9 and MCL1 inhibitors in lung cancer cells.

Kabir, Shaheen / Cidado, Justin / Andersen, Courtney / Dick, Cortni / Lin, Pei-Chun / Mitros, Therese / Ma, Hong / Baik, Seung Hyun / Belmonte, Matthew A / Drew, Lisa / Corn, Jacob E

eLife

2019 Volume 8

Abstract: Overexpression of anti-apoptotic proteins MCL1 and Bcl-xL are frequently observed in many cancers. Inhibitors targeting MCL1 are in clinical development, however numerous cancer models are intrinsically resistant to this approach. To discover mechanisms ... ...

Abstract	Overexpression of anti-apoptotic proteins MCL1 and Bcl-xL are frequently observed in many cancers. Inhibitors targeting MCL1 are in clinical development, however numerous cancer models are intrinsically resistant to this approach. To discover mechanisms underlying resistance to MCL1 inhibition, we performed multiple flow-cytometry based genome-wide CRISPR screens interrogating two drugs that directly (MCL1i) or indirectly (CDK9i) target MCL1. Remarkably, both screens identified three components (CUL5, RNF7 and UBE2F) of a cullin-RING ubiquitin ligase complex (CRL5) that resensitized cells to MCL1 inhibition. We find that levels of the BH3-only pro-apoptotic proteins Bim and Noxa are proteasomally regulated by the CRL5 complex. Accumulation of Noxa caused by depletion of CRL5 components was responsible for re-sensitization to CDK9 inhibitor, but not MCL1 inhibitor. Discovery of a novel role of CRL5 in apoptosis and resistance to multiple types of anticancer agents suggests the potential to improve combination treatments.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Bcl-2-Like Protein 11/genetics ; Cell Line, Tumor ; Cullin Proteins/genetics ; Cyclin-Dependent Kinase 9/antagonists & inhibitors ; Cyclin-Dependent Kinase 9/genetics ; Drug Resistance, Neoplasm/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors ; Myeloid Cell Leukemia Sequence 1 Protein/genetics ; Proto-Oncogene Proteins c-bcl-2/genetics ; Ubiquitin-Protein Ligase Complexes/genetics ; Ubiquitin-Protein Ligases/genetics
Chemical Substances	Antineoplastic Agents ; BCL2 protein, human ; Bcl-2-Like Protein 11 ; CUL5 protein, human ; Cullin Proteins ; MCL1 protein, human ; Myeloid Cell Leukemia Sequence 1 Protein ; PMAIP1 protein, human ; Proto-Oncogene Proteins c-bcl-2 ; Ubiquitin-Protein Ligase Complexes (EC 2.3.2.23) ; RNF7 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; CDK9 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 9 (EC 2.7.11.22)
Language	English
Publishing date	2019-07-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.44288
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Article ; Online: BCL2 blockade overcomes MCL1 resistance in multiple myeloma.

Siu, Ka Tat / Huang, Cherrie / Panaroni, Cristina / Mukaihara, Kenta / Fulzele, Keertik / Soucy, Rosemary / Thorburn, Cassandra / Cidado, Justin / Drew, Lisa / Chattopadhyay, Shrikanta / Raje, Noopur

Leukemia

2019 Volume 33, Issue 8, Page(s) 2098–2102

MeSH term(s)	Antineoplastic Agents/therapeutic use ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Cellular Microenvironment ; Drug Resistance, Neoplasm ; Humans ; Macrocyclic Compounds/therapeutic use ; Multiple Myeloma/drug therapy ; Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Sulfonamides/therapeutic use
Chemical Substances	AZD5991 ; Antineoplastic Agents ; Bridged Bicyclo Compounds, Heterocyclic ; MCL1 protein, human ; Macrocyclic Compounds ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2 ; Sulfonamides ; venetoclax (N54AIC43PW)
Language	English
Publishing date	2019-02-28
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-019-0421-0
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Zs.A 2295: Show issues

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Article ; Online: Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations.

Bashi, Azadeh C / Coker, Elizabeth A / Bulusu, Krishna C / Jaaks, Patricia / Crafter, Claire / Lightfoot, Howard / Milo, Marta / McCarten, Katrina / Jenkins, David F / van der Meer, Dieudonne / Lynch, James T / Barthorpe, Syd / Andersen, Courtney L / Barry, Simon T / Beck, Alexandra / Cidado, Justin / Gordon, Jacob A / Hall, Caitlin / Hall, James /

Mali, Iman / Mironenko, Tatiana / Mongeon, Kevin / Morris, James / Richardson, Laura / Smith, Paul D / Tavana, Omid / Tolley, Charlotte / Thomas, Frances / Willis, Brandon S / Yang, Wanjuan / O'Connor, Mark J / McDermott, Ultan / Critchlow, Susan E / Drew, Lisa / Fawell, Stephen E / Mettetal, Jerome T / Garnett, Mathew J

Cancer discovery

2024 Volume 14, Issue 5, Page(s) 846–865

Abstract: Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable ... ...

Abstract	Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific "emergent" biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets. Significance: We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of "emergent" combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses. This article is featured in Selected Articles from This Issue, p. 695.
MeSH term(s)	Humans ; Cell Line, Tumor ; Neoplasms/drug therapy ; Neoplasms/pathology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Drug Screening Assays, Antitumor/methods ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2024-03-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-23-0388
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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Order via subito

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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