RNAi-based screening of the human kinome identifies Akt-cooperating kinases: a new approach to designing efficacious multitargeted kinase inhibitors.
Tumors comprise genetically heterogeneous cell populations, whose growth and survival depend on multiple signaling pathways. This has spurred the development of multitargeted therapies, including small molecules that can inhibit multiple kinases. A major challenge in designing such molecules is to determine which kinases to inhibit in each cancer to maximize efficacy and therapeutic index. We describe an approach to this problem implementing RNA interference technology. In order to identify Akt-cooperating kinases, we screened a library of kinase-directed small interfering RNAs (siRNAs) for enhanced cancer cell killing in the presence of Akt inhibitor A-443654. siRNAs targeting casein kinase I gamma 3 (CSNK1G3) or the inositol polyphosphate multikinase (IPMK) significantly enhanced A-443654-mediated cell killing, and caused decreases in Akt Ser-473 and ribosomal protein S6 phosphorylation. Small molecules targeting CSNK1G3 and/or IPMK in addition to Akt may thus exhibit increased efficacy and have the potential for improved therapeutic index.
Morgan-Lappe
S
S
Abbott Laboratories, Cancer Research, Abbott Park, IL 60064, USA.
Woods
K W
KW
Li
Q
Q
Anderson
M G
MG
Schurdak
M E
ME
Luo
Y
Y
Giranda
V L
VL
Fesik
S W
SW
Leverson
J D
JD
D000970:Antineoplastic Agents / Q000494:pharmacology; D047389:Casein Kinase I / Q000096:biosynthesis* / Q000235:genetics; D016923:Cell Death; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes; D009369:Neoplasms / Q000235:genetics; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction
C504035:A 443654; D000970:Antineoplastic Agents; D007191:Indazoles; D007211:Indoles; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D017853:Phosphotransferases (Alcohol Group Acceptor); C434257:inositol polyphosphate multikinase; D047389:Casein Kinase I; D051057:Proto-Oncogene Proteins c-akt