TY - JOUR
T1 - RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia
AU - Tyner, Jeffrey W.
AU - Walters, Denise K.
AU - Willis, Stephanie G.
AU - Luttropp, Mary
AU - Oost, Jason
AU - Loriaux, Marc
AU - Erickson, Heidi
AU - Corbin, Amie S.
AU - O'Hare, Thomas
AU - Heinrich, Michael C.
AU - Deininger, Michael W.
AU - Druker, Brian J.
PY - 2008/2/15
Y1 - 2008/2/15
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=41349095906&partnerID=8YFLogxK
U2 - 10.1182/blood-2007-06-097253
DO - 10.1182/blood-2007-06-097253
M3 - Article
C2 - 18025156
AN - SCOPUS:41349095906
SN - 0006-4971
VL - 111
SP - 2238
EP - 2245
JO - Blood
JF - Blood
IS - 4
ER -