Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0026764 (
multiple myeloma
)
36,148
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
A paucity of validated kinase targets in human
multiple myeloma
has delayed clinical deployment of kinase inhibitors in treatment strategies. We therefore conducted a kinome-wide small interfering RNA (siRNA) lethality study in
myeloma
tumor lines bearing common t(4;14), t(14;16), and t(11;14) translocations to identify critically vulnerable kinases in
myeloma
tumor cells without regard to preconceived mechanistic notions. Fifteen kinases were repeatedly vulnerable in
myeloma
cells, including AKT1, AK3L1, AURKA, AURKB, CDC2L1, CDK5R2, FES, FLT4, GAK, GRK6,
HK1
, PKN1, PLK1, SMG1, and TNK2. Whereas several kinases (PLK1,
HK1
) were equally vulnerable in epithelial cells, others and particularly G protein-coupled receptor kinase, GRK6, appeared selectively vulnerable in
myeloma
. GRK6 inhibition was lethal to 6 of 7
myeloma
tumor lines but was tolerated in 7 of 7 human cell lines. GRK6 exhibits lymphoid-restricted expression, and from coimmunoprecipitation studies we demonstrate that expression in
myeloma
cells is regulated via direct association with the heat shock protein 90 (HSP90) chaperone. GRK6 silencing causes suppression of signal transducer and activator of transcription 3 (STAT3) phosphorylation associated with reduction in MCL1 levels and phosphorylation, illustrating a potent mechanism for the cytotoxicity of GRK6 inhibition in
multiple myeloma
(MM) tumor cells. As mice that lack GRK6 are healthy, inhibition of GRK6 represents a uniquely targeted novel therapeutic strategy in human
multiple myeloma
.
...
PMID:Kinome-wide RNAi studies in human multiple myeloma identify vulnerable kinase targets, including a lymphoid-restricted kinase, GRK6. 1999 89
Since Warburg's observation that most cancers exhibit elevated glycolysis, decades of research have attempted to reduce tumor glucose utilization as a therapeutic approach. Hexokinase (HK) activity is the first glycolytic enzymatic step; despite many attempts to inhibit HK activity, none has reached clinical application. Identification of HK isoforms, and recognition that most tissues express only
HK1
while most tumors express
HK1
and HK2, stimulated reducing HK2 activity as a therapeutic option. However, studies using HK2 shRNA and isogenic
HK1
+
HK2
-
and
HK1
+
HK2
+
tumor cell pairs demonstrated that tumors expressing only
HK1
, while exhibiting reduced glucose consumption, progressed
in vivo
as well as tumors expressing both
HK1
and HK2. However,
HK1
-
HK2
+
tumor subpopulations exist among many cancers. shRNA HK2 suppression in
HK1
-
HK2
+
liver cancer cells reduced xenograft tumor progression, in contrast to
HK1
+
HK2
+
cells. HK2 inhibition, and partial inhibition of both oxidative phosphorylation and fatty acid oxidation using HK2 shRNA and small-molecule drugs, prevented human liver
HK1
-
HK2
+
cancer xenograft progression. Using human
multiple myeloma
xenografts and mouse allogeneic models to identify potential clinical translational agents, triple therapies that include antisense HK2 oligonucleotides, metformin, and perhexiline prevent progression. These results suggest an agnostic approach for
HK1
-
HK2
+
cancers, regardless of tissue origin.
...
PMID:A Tumor Agnostic Therapeutic Strategy for Hexokinase 1-Null/Hexokinase 2-Positive Cancers. 3143 45
