RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia

• Published in: Blood Vol. 111; no. 4; pp. 2238 - 2245
• Main Authors: Tyner, Jeffrey W., Walters, Denise K., Willis, Stephanie G., Luttropp, Mary, Oost, Jason, Loriaux, Marc, Erickson, Heidi, Corbin, Amie S., O'Hare, Thomas, Heinrich, Michael C., Deininger, Michael W., Druker, Brian J.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.02.2008; The Americain Society of Hematology; American Society of Hematology
• Series: Neoplasia
• Subjects: Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Cell Line, Tumor; Gene Library; Hematologic and hematopoietic diseases; Humans; Janus Kinase 1 - genetics; Janus Kinase 3 - genetics; K562 Cells; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Neoplasia; Protein-Tyrosine Kinases - genetics; RNA Interference - physiology; RNA, Small Interfering - genetics; Tyrosine; Gene silencing; Acute myelogenous leukemia; RNA interference; Targeting; Hematology; Targeted therapy; Aminoacid; Malignant hemopathy; Medical screening; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-06-097253

Despite vast improvements in our understanding of cancer genetics, a large percentage of cancer cases present without knowledge of the causative genetic events. Tyrosine kinases are frequently implicated in the pathogenesis of numerous types of cancer, but identification and validation of tyrosine kinase targets in cancer can be a time-consuming process. We report the establishment of an efficient, functional screening assay using RNAi technology to directly assess and compare the effect of individually targeting each member of the tyrosine kinase family. We demonstrate that siRNA screening can identify tyrosine kinase targets containing activating mutations in Janus kinase (JAK) 3 (A572V) in CMK cells and c-KIT (V560G) in HMC1.1 cells. In addition, this assay identifies targets that do not contain mutations, such as JAK1 and the focal adhesion kinases (FAK), that are crucial to the survival of the cancer cells. This technique, with additional development, might eventually offer the potential to match specific therapies with individual patients based on a functional assay.