Treatment of human pre-B acute lymphoblastic leukemia with the Aurora kinase inhibitor PHA-739358 (Danusertib)
1 Section of Molecular Carcinogenesis, Division of Hematology/Oncology and The Saban Research Institute of Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
2 Current address: Laura Bassi Centre of Expertise, Theraped/Forschungsprogramm für Rezeptorbiochemie und Tumorstoffwechsel, Universitätsklinik für Kinder- und Jugendheilkunde, Paracelsus Medizinische Privatuniversität, Vienna, Austria
3 Department of Cell Biology, Nerviano Medical Sciences, Nerviano, MI, I-20014, Italy
4 Leukemia Research Program, Children’s Hospital Los Angeles, Los Angeles, USA
5 Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA USA
6 Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
7 Division of Hematology/Oncology, Ms#54, Children’s Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA
Molecular Cancer 2012, 11:42 doi:10.1186/1476-4598-11-42Published: 21 June 2012
Treatment 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.
We 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.
PHA-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.