TY - JOUR
T1 - Dual targeting of Aurora kinases with AMG 900 exhibits potent preclinical activity against acute myeloid leukemia with distinct post-mitotic outcomes
AU - Payton, Marc
AU - Cheung, Hung Kam
AU - Ninniri, Maria Stefania S.
AU - Marinaccio, Christian
AU - Wayne, William C.
AU - Hanestad, Kelly
AU - Crispino, John D.
AU - Juan, Gloria
AU - Coxon, Angela
N1 - Funding Information:
The authors thank individuals on AMG 900 project and specifically Stephanie Geuns-Meyer, Kathleen Keegan, Gregory Friberg, Erick Gamelin, Richard Kendall, Peter Pieslor, and Florian Vogl. We thank Ann Mullally at Brigham and Women's Hospital/Harvard Medical School for providing the Jak2V617Fmice. This work was supported in part by a grant from the NIH (HL112792) to JDC. We would also like to acknowledge the team from Molecular Imaging Inc. and inviCRO Inc. for conducting the in vivo imaging studies.
Funding Information:
The authors thank individuals on AMG 900 project and specifically Stephanie Geuns-Meyer, Kathleen Keegan, Gregory Friberg, Erick Gamelin, Richard Kendall, Peter Pieslor, and Florian Vogl. We thank Ann Mullally at Brigham and Women's Hospital/Harvard Medical School for providing the Jak2V617F mice. This work was supported in part by a grant from the NIH (HL112792) to JDC. We would also like to acknowledge the team from Molecular Imaging Inc. and inviCRO Inc. for conducting the in vivo imaging studies.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/12
Y1 - 2018/12
N2 - Aurora kinase A and B have essential and non-overlapping roles in mitosis, with elevated expression in a subset of human cancers, including acute myeloid leukemia (AML). In this study, pan-aurora kinase inhibitor (AKI) AMG 900 distinguishes itself as an anti-leukemic agent that is more uniformly potent against a panel of AML cell lines than are isoform-selective AKIs and classic AML drugs. AMG 900 inhibited AML cell growth by inducing polyploidization and/or apoptosis. AMG 900 and aurora-B–selective inhibitor AZD1152-hQPA showed comparable cellular effects on AML lines that do not harbor a FLT3-ITD mutation. AMG 900 was active against P-glycoprotein–expressing AML cells resistant to AZD1152-hQPA and was effective at inducing expression of megakaryocyte-lineage markers (CD41, CD42) on human CHRF-288-11 cells and mouse Jak2V617F cells. In MOLM-13 cells, inhibition of p-histone H3 by AMG 900 was associated with polyploidy, extra centrosomes, accumulation of p53 protein, apoptosis, and cleavage of Bcl-2 protein. Co-administration of cytarabine (Ara-C) with AMG 900 potentiated cell killing in a subset of AML lines, with evidence of attenuated polyploidization. AMG 900 inhibited the proliferation of primary human bone marrow cells in culture, with a better proliferation recovery profile relative to classic antimitotic drug docetaxel. In vivo, AMG 900 significantly reduced tumor burden in a systemic MOLM-13 xenograft model where we demonstrate the utility of 30-deoxy-30-18F-fluorothymidine [18F]FLT positron emission tomographic (PET)–CT imaging to measure the antiproliferative effects of AMG 900 in skeletal tissues in mice.
AB - Aurora kinase A and B have essential and non-overlapping roles in mitosis, with elevated expression in a subset of human cancers, including acute myeloid leukemia (AML). In this study, pan-aurora kinase inhibitor (AKI) AMG 900 distinguishes itself as an anti-leukemic agent that is more uniformly potent against a panel of AML cell lines than are isoform-selective AKIs and classic AML drugs. AMG 900 inhibited AML cell growth by inducing polyploidization and/or apoptosis. AMG 900 and aurora-B–selective inhibitor AZD1152-hQPA showed comparable cellular effects on AML lines that do not harbor a FLT3-ITD mutation. AMG 900 was active against P-glycoprotein–expressing AML cells resistant to AZD1152-hQPA and was effective at inducing expression of megakaryocyte-lineage markers (CD41, CD42) on human CHRF-288-11 cells and mouse Jak2V617F cells. In MOLM-13 cells, inhibition of p-histone H3 by AMG 900 was associated with polyploidy, extra centrosomes, accumulation of p53 protein, apoptosis, and cleavage of Bcl-2 protein. Co-administration of cytarabine (Ara-C) with AMG 900 potentiated cell killing in a subset of AML lines, with evidence of attenuated polyploidization. AMG 900 inhibited the proliferation of primary human bone marrow cells in culture, with a better proliferation recovery profile relative to classic antimitotic drug docetaxel. In vivo, AMG 900 significantly reduced tumor burden in a systemic MOLM-13 xenograft model where we demonstrate the utility of 30-deoxy-30-18F-fluorothymidine [18F]FLT positron emission tomographic (PET)–CT imaging to measure the antiproliferative effects of AMG 900 in skeletal tissues in mice.
UR - http://www.scopus.com/inward/record.url?scp=85057580757&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85057580757&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-18-0186
DO - 10.1158/1535-7163.MCT-18-0186
M3 - Article
C2 - 30266802
AN - SCOPUS:85057580757
SN - 1535-7163
VL - 17
SP - 2575
EP - 2585
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 12
ER -
