Role of CYP3A4 in bone marrow microenvironment–mediated protection of FLT3/ITD AML from tyrosine kinase inhibitors by Yu-Ting Chang, Daniela Hernandez,

Slides:

Advertisements

Similar presentations

PARPi-FL - a Fluorescent PARP1 Inhibitor for Glioblastoma Imaging

Advertisements

STAT3 mediates oncogenic addiction to TEL-AML1 in t(12;21) acute lymphoblastic leukemia by Maurizio Mangolini, Jasper de Boer, Vanessa Walf-Vorderwülbecke,

Identification of key regulatory pathways of myeloid differentiation using an mESC-based karyotypically normal cell model by Dong Li, Hong Yang, Hong Nan,

Protein kinase B (PKB/c-akt) regulates homing of hematopoietic progenitors through modulation of their adhesive and migratory properties by Miranda Buitenhuis,

The PP2A inhibitor SET regulates granzyme B expression in human natural killer cells by Rossana Trotta, David Ciarlariello, Jessica Dal Col, Hsiaoyin Mao,

Growth differentiating factor 15 enhances the tumor-initiating and self-renewal potential of multiple myeloma cells by Toshihiko Tanno, Yiting Lim, Qiuju.

by Ji-Long Chen, Andre Limnander, and Paul B. Rothman

Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML by Jianbiao.

STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma by Christine Brender, Mette Nielsen, Keld Kaltoft, Gitte Mikkelsen, Qian.

Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8)‏

A next-generation sequencing–based assay for minimal residual disease assessment in AML patients with FLT3-ITD mutations by Mark J. Levis, Alexander E.

Yongping Shao, Kaitlyn Le, Hanyin Cheng, Andrew E. Aplin

Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia by Xue-Fei Huang, Shao-Kai Luo,

by Daniel Sasca, Patricia S

by Daniela Buglio, Noor M

Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy by Mark P. Chao, Chad Tang, Russell K. Pachynski,

In vivo RNAi screening identifies Pafah1b3 as a target for combination therapy with TKIs in BCR-ABL1+ BCP-ALL by Eleanor R. C. Fiedler, Arjun Bhutkar,

Hyaluronate-Enhanced Hematopoiesis: Two Different Receptors Trigger the Release of Interleukin-1β and Interleukin-6 From Bone Marrow Macrophages by Sophia.

FLT3-ITD and TLR9 use Bruton tyrosine kinase to activate distinct transcriptional programs mediating AML cell survival and proliferation by Thomas Oellerich,

Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies.

Vascular endothelial growth factor stimulates protein kinase CβII expression in chronic lymphocytic leukemia cells by Simon T. Abrams, Benjamin R. B. Brown,

The exosome complex establishes a barricade to erythroid maturation

by Bindu Varghese, Adam Widman, James Do, Behnaz Taidi, Debra K

EPHB4 is a therapeutic target in AML and promotes leukemia cell survival via AKT by Akil A. Merchant, Aparna Jorapur, Amy McManus, Ren Liu, Valery Krasnoperov,

Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival by Kyu-Tae Kim, Kristin Baird, Joon-Young Ahn, Paul.

Effects of SC144 on in vivo ovarian tumor.

Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia by Parvathi Ranganathan, Xueyan Yu, Caroline Na, Ramasamy Santhanam, Sharon Shacham,

DQ661 improves survival in colon cancer model and potentiates activity of gemcitabine in KPC pancreatic cancer syngeneic model. DQ661 improves survival.

by Hairui Su, Chiao-Wang Sun, Szu-Mam Liu, Xin He, Hao Hu, Kevin M

by James J. Ignatz-Hoover, Victoria Wang, Nathan M. Mackowski, Anne J

Enhancing functional platelet release in vivo from in vitro–grown megakaryocytes using small molecule inhibitors by Danuta Jarocha, Karen K. Vo, Randolph.

Crosstalk between ROR1 and BCR pathways defines novel treatment strategies in mantle cell lymphoma by Hanna Karvonen, David Chiron, Wilhelmiina Niininen,

The EGF receptor confers BRAF inhibitor resistance in BRAF-mutant melanoma cells. The EGF receptor confers BRAF inhibitor resistance in BRAF-mutant melanoma.

by Adrienne Sallets, Sophie Robinson, Adel Kardosh, and Ronald Levy

by Kamira Maharaj, John J

Merlin-deficient RAS-mutant cells and murine PDTCs are more sensitive to MEK inhibition. Merlin-deficient RAS-mutant cells and murine PDTCs are more sensitive.

Fig. 7 BRD0705 impairs colony formation in AML cell lines and patient cells and shows in vivo efficacy in multiple AML mouse models. BRD0705 impairs colony.

RUNX transcription factors potentially control E-selectin expression in the bone marrow vascular niche in mice by Ken Morita, Chieko Tokushige, Shintaro.

Imetelstat, a telomerase inhibitor, is capable of depleting myelofibrosis stem and progenitor cells by Xiaoli Wang, Cing Siang Hu, Bruce Petersen, Jiajing.

The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy by Suhu Liu, Anna E. Marneth, Gabriela.

P53 inhibition impairs expansion of HSCs with VPA by increasing ROS levels. p53 inhibition impairs expansion of HSCs with VPA by increasing ROS levels.

Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells by Mia Eriksson, Pablo Peña-Martínez,

MLL-AF9 leukemias are sensitive to PARP1 inhibitors combined with cytotoxic drugs by Silvia Maifrede, Esteban Martinez, Margaret Nieborowska-Skorska, Daniela.

Myeloma cell–derived Runx2 promotes myeloma progression in bone

Kruppel-like factor 4 regulates neutrophil activation

Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase by Sarah E. Fordham, Helen.

Two distinct CXCR4 antagonists mobilize progenitor cells in mice by different mechanisms by Andia N. Redpath, Moïra François, Suet-Ping Wong, Dominique.

Paradoxical enhancement of leukemogenesis in acute myeloid leukemia with moderately attenuated RUNX1 expressions by Ken Morita, Shintaro Maeda, Kensho.

by Tadayuki Yago, Nan Zhang, Liang Zhao, Charles S

A novel CXCR4 antagonist IgG1 antibody (PF ) for the treatment of hematologic malignancies by Shu-Hui Liu, Yin Gu, Bernadette Pascual, Zhengming.

Targeting ubiquitin-activating enzyme induces ER stress–mediated apoptosis in B-cell lymphoma cells by Scott Best, Taylor Hashiguchi, Adam Kittai, Nur.

Interleukin-2–inducible T-cell kinase inhibitors modify functional polarization of human peripheral T-cell lymphoma cells by Sami Mamand, Matthew Carr,

by Kelly E. Johnson, Julia R. Ceglowski, Harvey G. Roweth, Jodi A

AML cells display differential sensitivity to inhibition of IKBKE and TBK1. AML cells display differential sensitivity to inhibition of IKBKE and TBK1.

eIF5A-PEAK1 signaling regulates KRAS protein expression.

ONC201 activates the ISR. ONC201 activates the ISR. (A) Western blotting analysis for ATF4, CHOP, ATF3, and TRB3 on lysates from HCT116 cells cultured.

by Pamela J. Sung, Mayumi Sugita, Holly Koblish, Alexander E

IL-6 signaling affects response to erlotinib in head and neck (HNSCC) cells. IL-6 signaling affects response to erlotinib in head and neck (HNSCC) cells.

Correlation of MAGE-A1 expression with PFS in patients treated with FRD and knockdown of MAGE-A in HMCLs. MAGE-A1 expression is correlated with resistance.

TH-302 has antileukemia activity in an in vivo primary AML xenograft murine model. TH-302 has antileukemia activity in an in vivo primary AML xenograft.

The SFKs confer BRAF inhibitor resistance in BRAF-mutant melanoma cells. The SFKs confer BRAF inhibitor resistance in BRAF-mutant melanoma cells. A, phospho-protein.

Fig. 8 C9orf72 knockdown results in an increase in autophagic flux.

IDO deficiency delays the development of pulmonary metastases.

Bone marrow stroma partially protects multiple myeloma and AML cell lines from tipifarnib- and bortezomib-induced cell death. 8226/S myeloma cells were.

GM-CSF is required for CA-MSC–induced tumor metastasis.

Activity of a chemically modified miR-21 inhibitor in human bladder cancer xenografts. Activity of a chemically modified miR-21 inhibitor in human bladder.

RhuαVEGF and rhuαVEGF/paclitaxel mediated growth inhibition in an androgen-independent prostate cancer xenograft model. rhuαVEGF and rhuαVEGF/paclitaxel.

BH3-targeted inhibitors drive specific resistance in human cell lines, which can be overcome with alternating or combining inhibitors. BH3-targeted inhibitors.

AMG 176 exhibits robust single-agent activity in vivo.

AXL knockout does not prevent dormancy.

Presentation transcript:

Role of CYP3A4 in bone marrow microenvironment–mediated protection of FLT3/ITD AML from tyrosine kinase inhibitors by Yu-Ting Chang, Daniela Hernandez, Salvador Alonso, Minling Gao, Meng Su, Gabriel Ghiaur, Mark J. Levis, and Richard J. Jones BloodAdv Volume 3(6):908-916 March 26, 2019 © 2019 by The American Society of Hematology

Yu-Ting Chang et al. Blood Adv 2019;3:908-916 © 2019 by The American Society of Hematology

Knockdown of CYP3A4 in BMSCs reversed the stromal-mediated FLT3 TKI resistance of FLT3/ITD AML cells. Knockdown of CYP3A4 in BMSCs reversed the stromal-mediated FLT3 TKI resistance of FLT3/ITD AML cells. Clonogenic recovery of MV4-11 (A) and Molm14 (B) cells when cultured without F/STRO (Liq), with control F/STRO (CT Stro), or with shRNA CYP3A4 knockdown F/STRO (KD Stro) after treatment with 3 different FLT3 TKIs (20 nM sorafenib, 0.5 nM quizartinib, and 20 nM gilteritinib) for 72 hours. Data represent mean ± standard error of the mean (SEM) of 3 to 4 independent experiments. *P < .05, **P < .01, ***P < .001. CFU, colony-forming unit. Yu-Ting Chang et al. Blood Adv 2019;3:908-916 © 2019 by The American Society of Hematology

CYP3A4 in BMSCs blocked the inhibitory activity of FLT3 TKIs in FLT3/ITD AML in the absence of AML–stromal cellular contact. CYP3A4 in BMSCs blocked the inhibitory activity of FLT3 TKIs in FLT3/ITD AML in the absence of AML–stromal cellular contact. (A) Expression of phosphorylated FLT3 (P-FLT3) and total FLT3 (T-FLT3) in Molm14 cells by western blotting after 1 hour of incubation with 3 different FLT3 TKIs (20 nM sorafenib, 20 nM gilteritinib, and 3.5 nM quizartinib) that had been incubated with or without bone marrow stroma for 72 hours. The left 3 control lanes are conditioned media without TKIs (just DMSO). (B) Quantification of phosphorylated FLT3 in Molm14 cells. Data are the mean ± SEM of 4 (sorafenib) and 5 (gilteritinib) independent experiments. Quantification of phosphorylated FLT3 with quizartinib treatment is not presented because the experiment was performed once. ***P < .001. CT Stro, control F/STRO; KD Stro, shRNA CYP3A4 knockdown F/STRO; Liq, no F/STRO. Yu-Ting Chang et al. Blood Adv 2019;3:908-916 © 2019 by The American Society of Hematology

Knockdown of CYP3A4 in BMSCs reduced the stromal-mediated FLT3 TKI resistance of FLT3/ITD AML in the mouse xenograft model. Knockdown of CYP3A4 in BMSCs reduced the stromal-mediated FLT3 TKI resistance of FLT3/ITD AML in the mouse xenograft model. (A) The right panel depicts the mouse xenograft model. Tumors on the left flanks were composed of luciferase-positive (Luc+) Molm14 cells and control human primary BMSCs (Control 1° stroma); tumors on the right flanks were composed of Luc+ Molm14 cells and human primary BMSCs with shRNA knockdown of CYP3A4 (shCYP3A4 1° stroma). Mice with xenograft tumors were treated with 10 mg/kg sorafenib 3 times per week for 4 weeks. The left panel shows the bioluminescent images representing tumor burden of 5 representative xenograft mice on day 0, day 14, and day 28 after the treatment started. (B) Fold change in the bioluminescent intensity of xenograft tumors with control or shCYP3A4 1° stroma on day 28 relative to day 0 during sorafenib treatment. Data represent the mean ± SEM of 10 independent xenografts. **P < .01. IP, intraperitoneal. Yu-Ting Chang et al. Blood Adv 2019;3:908-916 © 2019 by The American Society of Hematology

The CYP3A4 inhibitor clarithromycin reversed the stromal-mediated FLT3 TKI resistance of FLT3/ITD AML cells. The CYP3A4 inhibitor clarithromycin reversed the stromal-mediated FLT3 TKI resistance of FLT3/ITD AML cells. Clonogenic recovery of MV4-11 (A) and Molm14 (B) cells when cultured without (Liq) or with F/STRO (Stro) and without or with clarithromycin (+Cla) after treatment with 3 different FLT3 TKIs (20 nM sorafenib, 0.5 nM quizartinib, and 20 nM gilteritinib) for 72 hours. Data are the mean ± SEM of 3 to 4 independent experiments. *P < .05, **P < .01. Yu-Ting Chang et al. Blood Adv 2019;3:908-916 © 2019 by The American Society of Hematology