Protein Kinase Gene Expression Profiling and In Vitro Functional Experiments Identify Novel Potential Therapeutic Targets in Adult Acute Lymphoblastic Leukemia

BACKGROUND: Despite recent improvements in the treatment of acute lymphoblastic leukemia (ALL), adult patients still have an overall poor outcome. The future of ALL management relies on the introduction of novel targeted therapies. The authors sought to assess if protein kinases (PKs), frequently deregulated in cancer, show an altered expression pattern and can be considered as suitable therapeutic targets in adult ALL. METHODS: The authors studied the PK gene expression profile by oligonucleotide arrays in 133 adult ALL samples at the onset of the disease and subsequently performed in vitro experiments to evaluate the sensitivity to first- and second-generation PK inhibitors of a set of ALL cell lines, as well as of primary ALL cells. RESULTS: The study documents a distinctive PK signature for different adult ALL subgroups; the PKs identified include several tyrosine kinase (TK) genes, especially in E2A/PBX+ B-lineage ALL (B-ALL), B-ALL without known molecular abnormalities, and T-lineage ALL. Consistently, cell lines and primary samples belonging to these groups proved susceptible to TK inhibitors. CONCLUSIONS: These results indicate that second-generation TK inhibitors may be effective in ALL subsets other than BCR/ABL+ B-ALL and provide the rationale for testing the impact of the newly developed TK inhibitors in the management of adult ALL patients. Cancer 2010;116:3426-37. (C) 2010 American Cancer Society.