8 results on '"Po Yee Mak"'
Search Results
2. AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia
- Author
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Sean M. Post, Huaxian Ma, Prerna Malaney, Xiaorui Zhang, Marisa J.L. Aitken, Po Yee Mak, Vivian R. Ruvolo, Tomoko Yasuhiro, Ryohei Kozaki, Lauren E. Chan, Lauren B. Ostermann, Marina Konopleva, Bing Z. Carter, Courtney DiNardo, Michael D. Andreeff, Joseph D. Khoury, and Peter P. Ruvolo
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular- signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that overexpress MCL1. Proteomic analyses revealed that ABT-199-resistant cells expressed elevated levels of pro-growth and anti-apoptotic proteins compared to parental cells, and that ONO-7475 reduced the expression of these proteins in both the parental and ABT-199-resistant cells. ONO-7475 treatment significantly extended survival as a single in vivo agent using acute myeloid leukemia cell lines and PDX models. Compared to ONO-7474 monotherapy, the combination of ONO-7475/ABT-199 was even more potent in reducing leukemic burden and prolonging the survival of mice in both model systems. These results suggest that the ONO-7475/ABT-199 combination may be effective for AML therapy.
- Published
- 2021
- Full Text
- View/download PDF
3. Targeting MCL-1 dysregulates cell metabolism and leukemia-stroma interactions and re-sensitizes acute myeloid leukemia to BCL-2 inhibition
- Author
-
Bing Z. Carter, Po Yee Mak, Wenjing Tao, Marc Warmoes, Philip L. Lorenzi, Duncan Mak, Vivian Ruvolo, Lin Tan, Justin Cidado, Lisa Drew, and Michael Andreeff
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
MCL-1 and BCL-2 are both frequently overexpressed in acute myeloid leukemia (AML) and critical for the survival of AML cells and AML 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 AML cells and AML 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 AML patient who acquired resistance to venetoclax/decitabine. These results demonstrate that co-targeting MCL-1 and BCL-2 improves the efficacy of and overcomes pre-existing and acquired resistance to BCL-2 inhibition. Activation of metabolomic pathways and leukemia-stroma interactions are newly discovered functions of MCL-1 in AML, which are independent from canonical regulation of apoptosis by MCL-1. Our data provide new mechanisms of synergy and a rationale for co-targeting MCL-1 and BCL-2 clinically in patients with AML and potentially other cancers.
- Published
- 2020
- Full Text
- View/download PDF
4. Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model
- Author
-
Bing Z. Carter, Po Yee Mak, Hong Mu, Xiangmeng Wang, Wenjing Tao, Duncan H. Mak, Elisha J. Dettman, Michael Cardone, Oleg Zernovak, Takahiko Seki, and Michael Andreeff
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Although highly effective, BCR-ABL1 tyrosine kinase inhibitors do not target chronic myeloid leukemia (CML) stem cells. Most patients relapse upon tyrosine kinase inhibitor therapy cessation. We reported previously that combined BCR-ABL1 and BCL-2 inhibition synergistically targets CML stem/progenitor cells. p53 induces apoptosis mainly by modulating BCL-2 family proteins. Although infrequently mutated in CML, p53 is antagonized by MDM2, which is regulated by BCR-ABL1 signaling. We hypothesized that MDM2 inhibition could sensitize CML cells to tyrosine kinase inhibitors. Using an inducible transgenic Scl-tTa-BCR-ABL1 murine CML model, we found, by RT-PCR and CyTOF proteomics increased p53 signaling in CML bone marrow (BM) cells compared with controls in CD45+ and linage-SCA-1+C-KIT+ populations. CML BM cells were more sensitive to exogenous BH3 peptides than controls. Combined inhibition of BCR-ABL1 with imatinib and MDM2 with DS-5272 increased NOXA level, markedly reduced leukemic linage-SCA-1+C-KIT+ cells and hematopoiesis, decreased leukemia burden, significantly prolonged the survival of mice engrafted with BM cells from Scl-tTa-BCR-ABL1 mice, and significantly decreased CML stem cell frequency in secondary transplantations. Our results suggest that CML stem/progenitor cells have increased p53 signaling and a propensity for apoptosis. Combined MDM2 and BCR-ABL1 inhibition targets CML stem/progenitor cells and has the potential to improve cure rates for CML.
- Published
- 2020
- Full Text
- View/download PDF
5. AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill FLT3-ITD acute myeloid leukemia
- Author
-
Joseph D. Khoury, Prerna Malaney, Courtney D. DiNardo, Bing Z. Carter, Lauren B Ostermann, Michael Andreeff, Ryohei Kozaki, Xiaorui Zhang, Marina Konopleva, Sean M. Post, Marisa J.L. Aitken, Peter P. Ruvolo, Huaxian Ma, Vivian Ruvolo, Tomoko Yasuhiro, Po Yee Mak, and Lauren E. Chan
- Subjects
MAPK/ERK pathway ,Myeloid ,business.industry ,Venetoclax ,Myeloid leukemia ,Hematology ,MERTK ,medicine.disease ,Leukemia ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,hemic and lymphatic diseases ,medicine ,Cancer research ,MCL1 ,business ,Tyrosine kinase - Abstract
FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular- signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that overexpress MCL1. Proteomic analyses revealed that ABT-199-resistant cells expressed elevated levels of pro-growth and anti-apoptotic proteins compared to parental cells, and that ONO-7475 reduced the expression of these proteins in both the parental and ABT-199-resistant cells. ONO-7475 treatment significantly extended survival as a single in vivo agent using acute myeloid leukemia cell lines and PDX models. Compared to ONO-7474 monotherapy, the combination of ONO-7475/ABT-199 was even more potent in reducing leukemic burden and prolonging the survival of mice in both model systems. These results suggest that the ONO-7475/ABT-199 combination may be effective for AML therapy.
- Published
- 2021
6. Targeting MCL-1 dysregulates cell metabolism and leukemia-stroma interactions and re-sensitizes acute myeloid leukemia to BCL-2 inhibition
- Author
-
Lisa Drew, Justin Cidado, Michael Andreeff, Wenjing Tao, Po Yee Mak, Vivian Ruvolo, Marc O. Warmoes, Bing Z. Carter, Duncan Mak, Philip L. Lorenzi, and Lin Tan
- Subjects
Stromal cell ,Cell ,Decitabine ,Apoptosis ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Progenitor cell ,neoplasms ,030304 developmental biology ,Sulfonamides ,0303 health sciences ,Venetoclax ,Myeloid leukemia ,Hematology ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Myeloid Cell Leukemia Sequence 1 Protein ,Stem cell ,medicine.drug - 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.
- Published
- 2020
7. Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model
- Author
-
Duncan H. Mak, Michael H. Cardone, Wenjing Tao, Bing Z. Carter, Hong Mu, Elisha J. Dettman, Xiangmeng Wang, Po Yee Mak, Oleg Zernovak, Michael Andreeff, and Takahiko Seki
- Subjects
medicine.drug_class ,Chronic Myeloid Leukemia ,Fusion Proteins, bcr-abl ,Biology ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Animals ,Progenitor cell ,neoplasms ,Stem Cells ,Myeloid leukemia ,Imatinib ,Hematology ,Articles ,medicine.disease ,Haematopoiesis ,Leukemia ,Disease Models, Animal ,medicine.anatomical_structure ,Cancer research ,Bone marrow ,Stem cell ,030215 immunology ,medicine.drug - Abstract
Although highly effective, BCR-ABL1 tyrosine kinase inhibitors do not target chronic myeloid leukemia (CML) stem cells. Most patients relapse upon tyrosine kinase inhibitor therapy cessation. We reported previously that combined BCR-ABL1 and BCL-2 inhibition synergistically targets CML stem/progenitor cells. p53 induces apoptosis mainly by modulating BCL-2 family proteins. Although infrequently mutated in CML, p53 is antagonized by MDM2, which is regulated by BCR-ABL1 signaling. We hypothesized that MDM2 inhibition could sensitize CML cells to tyrosine kinase inhibitors. Using an inducible transgenic Scl-tTa-BCR-ABL1 murine CML model, we found, by RT-PCR and CyTOF proteomics increased p53 signaling in CML bone marrow (BM) cells compared with controls in CD45+ and linage-SCA-1+C-KIT+ populations. CML BM cells were more sensitive to exogenous BH3 peptides than controls. Combined inhibition of BCR-ABL1 with imatinib and MDM2 with DS-5272 increased NOXA level, markedly reduced leukemic linage-SCA-1+C-KIT+ cells and hematopoiesis, decreased leukemia burden, significantly prolonged the survival of mice engrafted with BM cells from Scl-tTa-BCR-ABL1 mice, and significantly decreased CML stem cell frequency in secondary transplantations. Our results suggest that CML stem/progenitor cells have increased p53 signaling and a propensity for apoptosis. Combined MDM2 and BCR-ABL1 inhibition targets CML stem/progenitor cells and has the potential to improve cure rates for CML.
- Published
- 2020
8. AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill
- Author
-
Sean M, Post, Huaxian, Ma, Prerna, Malaney, Xiaorui, Zhang, Marisa J L, Aitken, Po Yee, Mak, Vivian R, Ruvolo, Tomoko, Yasuhiro, Ryohei, Kozaki, Lauren E, Chan, Lauren B, Ostermann, Marina, Konopleva, Bing Z, Carter, Courtney, DiNardo, Michael D, Andreeff, Joseph D, Khoury, and Peter P, Ruvolo
- Subjects
Proteomics ,Sulfonamides ,c-Mer Tyrosine Kinase ,Apoptosis ,Bridged Bicyclo Compounds, Heterocyclic ,Leukemia, Myeloid, Acute ,Mice ,fms-Like Tyrosine Kinase 3 ,Drug Resistance, Neoplasm ,Cell Line, Tumor ,Animals ,Humans ,Myeloid Cell Leukemia Sequence 1 Protein ,Extracellular Signal-Regulated MAP Kinases ,Protein Kinase Inhibitors - Abstract
FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular- signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that overexpress MCL1. Proteomic analyses revealed that ABT-199-resistant cells expressed elevated levels of pro-growth and anti-apoptotic proteins compared to parental cells, and that ONO-7475 reduced the expression of these proteins in both the parental and ABT-199-resistant cells. ONO-7475 treatment significantly extended survival as a single in vivo agent using acute myeloid leukemia cell lines and PDX models. Compared to ONO-7474 monotherapy, the combination of ONO-7475/ABT-199 was even more potent in reducing leukemic burden and prolonging the survival of mice in both model systems. These results suggest that the ONO-7475/ABT-199 combination may be effective for AML therapy.
- Published
- 2020
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