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

Abstract

BACKGROUND:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Fei Fei, Min Lim, Sabine Schmidhuber, Jürgen Moll, John Groffen, Nora Heisterkamp
• Journal: Molecular cancer (Mol Cancer) Vol. 11 Pg. 42 (Jun 21 2012) ISSN: 1476-4598 [Electronic] England
• PMID: 22721004 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Protein Kinase Inhibitors
• Pyrazoles
• Vincristine
• Fusion Proteins, bcr-abl
• AURKB protein, human
• Aurkb protein, mouse
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases
• danusertib

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects, genetics)
• Aurora Kinase B
• Aurora Kinases
• Benzamides (administration & dosage, pharmacology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects, genetics)
• Drug Synergism
• Enzyme Activation (drug effects)
• Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics)
• Humans
• Mice
• Mutation
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism)
• Protein Kinase Inhibitors (administration & dosage, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Pyrazoles (administration & dosage, pharmacology)
• Vincristine (pharmacology)