RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia.
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.
Tyner
Jeffrey W
JW
Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute, Portland, USA.
Walters
Denise K
DK
Willis
Stephanie G
SG
Luttropp
Mary
M
Oost
Jason
J
Loriaux
Marc
M
Erickson
Heidi
H
Corbin
Amie S
AS
O'Hare
Thomas
T
Heinrich
Michael C
MC
Deininger
Michael W
MW
Druker
Brian J
BJ
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015723:Gene Library; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics; D053616:Janus Kinase 3 / Q000235:genetics; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D034622:RNA Interference / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3