Treatment of human pre-B acute lymphoblastic leukemia with the Aurora kinase inhibitor PHA-739358 (Danusertib)

Molecular Cancer

Research

Jürgen Moll¹  Min Lim²  Fei Fei²  Sabine Schmidhuber³  John Groffen⁴  Nora Heisterkamp⁵ 

[1] Department of Cell Biology, Nerviano Medical Sciences, I-20014, Nerviano, MI, Italy;Division of Hematology/Oncology and The Saban Research Institute of Children’s Hospital Los Angeles, Section of Molecular Carcinogenesis, 90027, Los Angeles, CA, USA;Division of Hematology/Oncology and The Saban Research Institute of Children’s Hospital Los Angeles, Section of Molecular Carcinogenesis, 90027, Los Angeles, CA, USA;Laura Bassi Centre of Expertise, Theraped/Forschungsprogramm für Rezeptorbiochemie und Tumorstoffwechsel, Universitätsklinik für Kinder- und Jugendheilkunde, Paracelsus Medizinische Privatuniversität, Vienna, Austria;Division of Hematology/Oncology and The Saban Research Institute of Children’s Hospital Los Angeles, Section of Molecular Carcinogenesis, 90027, Los Angeles, CA, USA;Leukemia Research Program, Children’s Hospital Los Angeles, Los Angeles, USA;Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, USA, Los Angeles, CA;Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, 90033, Los Angeles, CA, USA;Division of Hematology/Oncology and The Saban Research Institute of Children’s Hospital Los Angeles, Section of Molecular Carcinogenesis, 90027, Los Angeles, CA, USA;Leukemia Research Program, Children’s Hospital Los Angeles, Los Angeles, USA;Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, USA, Los Angeles, CA;Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, 90033, Los Angeles, CA, USA;Division of Hematology/Oncology, Ms#54, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, 90027, Los Angeles, CA, USA;

关键词: Ph-positive;    Aurora kinase inhibition;    Drug resistance;    Stromal support;    Co-culture;    Farnesyltransferase inhibitor, Lonafarnib;    Dasatinib, p53, Combination drug treatment;   

DOI  :  10.1186/1476-4598-11-42

 received in 2012-01-18, accepted in 2012-06-11,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundTreatment of Philadelphia chromosome-positive acute lymphoblastic leukemias (Ph-positive ALL) with clinically approved inhibitors of the Bcr/Abl tyrosine kinase frequently results in the emergence of a leukemic clone carrying the T315I mutation in Bcr/Abl, which confers resistance to these drugs. PHA-739358, an Aurora kinase inhibitor, was reported to inhibit the Bcr/Abl T315I mutant in CML cells but no preclinical studies have examined this in detail in human ALL.ResultsWe compared the sensitivity of human Bcr/Abl T315I, Bcr/Abl wild type and non-Bcr/Abl ALL cells to this drug. PHA-739358 inhibited proliferation and induced apoptosis independently of Bcr/Abl, the T315I mutation, or presence of the tumor suppressor p53, but the degree of effectiveness varied between different ALL samples. Since short-term treatment with a single dose of drug only transiently inhibited proliferation, we tested combination treatments of PHA-739358 with the farnesyltransferase inhibitor Lonafarnib, with vincristine and with dasatinib. All combinations reduced viability and cell numbers compared to treatment with a single drug. Clonogenic assays showed that 25 nM PHA-739358 significantly reduced the colony growth potential of Ph-positive ALL cells, and combined treatment with a second drug abrogated colony growth in this assay. PHA-739358 further effectively blocked Bcr/Abl tyrosine kinase activity and Aurora kinase B in vivo, and mice transplanted with human Bcr/Abl T315I ALL cells treated with a 3x 7-day cycle of PHA-739358 as mono-treatment had significantly longer survival.ConclusionsPHA-739358 represents an alternative drug for the treatment of both Ph-positive and negative ALL, although combined treatment with a second drug may be needed to eradicate the leukemic cells.

【 授权许可】

Unknown   
© Fei et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.