PMID- 33036022
OWN - NLM
STAT- MEDLINE
DCOM- 20210927
LR  - 20240226
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 137
IP  - 13
DP  - 2021 Apr 1
TI  - Targeting the GCK pathway: a novel and selective therapeutic strategy against 
      RAS-mutated multiple myeloma.
PG  - 1754-1764
LID - 10.1182/blood.2020006334 [doi]
AB  - In multiple myeloma (MM), frequent mutations of NRAS, KRAS, or BRAF are found in 
      up to 50% of newly diagnosed patients. The majority of the NRAS, KRAS, and BRAF 
      mutations occur in hotspots causing constitutive activation of the corresponding 
      proteins. Thus, targeting RAS mutation in MM will increase therapeutic efficiency 
      and potentially overcome drug resistance. We identified germinal center kinase 
      (GCK) as a novel therapeutic target in MM with RAS mutation. GCK knockdown (KD) 
      in MM cells demonstrated in vitro and in vivo that silencing of GCK induces MM 
      cell growth inhibition, associated with blocked MKK4/7-JNK phosphorylation and 
      impaired degradation of IKZF1/3, BCL-6, and c-MYC. These effects were rescued by 
      overexpression of a short hairpin RNA (shRNA)-resistant GCK, thereby excluding 
      the potential off-target effects of GCK KD. In contrast, overexpression of 
      shRNA-resistant GCK kinase-dead mutant (K45A) inhibited MM cell proliferation and 
      failed to rescue the effects of GCK KD on MM growth inhibition, indicating that 
      GCK kinase activity is critical for regulating MM cell proliferation and 
      survival. Importantly, the higher sensitivity to GCK KD in RASMut cells suggests 
      that targeting GCK is effective in MM, which harbors RAS mutations. In accordance 
      with the effects of GCK KD, the GCK inhibitor TL4-12 dose-dependently 
      downregulated IKZF1 and BCL-6 and led to MM cell proliferation inhibition 
      accompanied by induction of apoptosis. Here, our data identify GCK as a novel 
      target in RASMut MM cells, providing a rationale to treat RAS mutations in MM. 
      Furthermore, GCK inhibitors might represent an alternative therapy to overcome 
      immunomodulatory drug resistance in MM.
CI  - (c) 2021 by The American Society of Hematology.
FAU - Li, Shirong
AU  - Li S
AD  - Department of Medicine and.
FAU - Fu, Jing
AU  - Fu J
AD  - Department of Medicine and.
FAU - Yang, Jun
AU  - Yang J
AD  - Department of Medicine and.
FAU - Ma, Huihui
AU  - Ma H
AD  - Columbia Center for Translational Immunology, College of Physicians and Surgeons, 
      Columbia University, New York, NY; and.
FAU - Bhutani, Divaya
AU  - Bhutani D
AD  - Department of Medicine and.
FAU - Mapara, Markus Y
AU  - Mapara MY
AD  - Columbia Center for Translational Immunology, College of Physicians and Surgeons, 
      Columbia University, New York, NY; and.
FAU - Marcireau, Christophe
AU  - Marcireau C
AD  - Sanofi, Paris, France.
FAU - Lentzsch, Suzanne
AU  - Lentzsch S
AD  - Department of Medicine and.
LA  - eng
GR  - S10 OD020056/OD/NIH HHS/United States
GR  - R01 HL093716/HL/NHLBI NIH HHS/United States
GR  - UL1 TR001873/TR/NCATS NIH HHS/United States
GR  - R01 CA175313/CA/NCI NIH HHS/United States
GR  - S10 RR027050/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Germinal Center Kinases)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - *Gene Silencing
MH  - Genetic Therapy
MH  - Germinal Center Kinases/*genetics/metabolism
MH  - Humans
MH  - Mice, SCID
MH  - Molecular Targeted Therapy
MH  - Multiple Myeloma/genetics/metabolism/*therapy
MH  - Mutation/drug effects
MH  - Protein Kinase Inhibitors/pharmacology/*therapeutic use
MH  - Signal Transduction/drug effects
MH  - ras Proteins/*genetics
MH  - Mice
PMC - PMC8020269
COIS- Conflict-of-interest disclosure: S. Lentzsch reports Caelum Biosciences equity 
      ownership and membership on Caelum Bioscience's board of directors or advisory 
      committees; consultancy for Janssen, Takeda, GSK, Antengene, Adaptive and 
      Sorrento; and received research funding from Karyopharm and Sanofi. M.Y.M. 
      reports receiving research funding from Ossium Health, Inc and  consultancy for 
      Ossium Health. C.M. is a full-time employee of Sanofi. The remaining authors 
      declare no competing financial interests.
EDAT- 2020/10/10 06:00
MHDA- 2021/09/28 06:00
PMCR- 2022/04/01
CRDT- 2020/10/09 20:19
PHST- 2020/04/22 00:00 [received]
PHST- 2020/09/25 00:00 [accepted]
PHST- 2020/10/10 06:00 [pubmed]
PHST- 2021/09/28 06:00 [medline]
PHST- 2020/10/09 20:19 [entrez]
PHST- 2022/04/01 00:00 [pmc-release]
AID - S0006-4971(21)00723-0 [pii]
AID - 2020/BLD2020006334 [pii]
AID - 10.1182/blood.2020006334 [doi]
PST - ppublish
SO  - Blood. 2021 Apr 1;137(13):1754-1764. doi: 10.1182/blood.2020006334.