PMID- 37951219
OWN - NLM
STAT- MEDLINE
DCOM- 20231127
LR  - 20240212
IS  - 2666-3791 (Electronic)
IS  - 2666-3791 (Linking)
VI  - 4
IP  - 11
DP  - 2023 Nov 21
TI  - HOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis 
      pathway by regulating MSK1 and PPP2R2B.
PG  - 101285
LID - S2666-3791(23)00479-2 [pii]
LID - 10.1016/j.xcrm.2023.101285 [doi]
LID - 101285
AB  - Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which 
      lacks effective therapies. Here, we demonstrate that the transcription factor, 
      homeobox C6 (HOXC6), is overexpressed in most PDACs, and its inhibition blocks 
      PDAC tumor growth and metastasis. HOXC6 transcriptionally activates 
      tumor-promoting kinase MSK1 and suppresses tumor-inhibitory protein PPP2R2B in 
      PDAC. HOXC6-induced PPP2R2B suppression causes mammalian target of rapamycin 
      (mTOR) pathway activation, which facilitates PDAC growth. Also, MSK1 upregulation 
      by HOXC6 is necessary for PDAC growth because of its ability to suppress 
      apoptosis via its substrate DDX17. Combinatorial pharmacological inhibition of 
      MSK1 and mTOR potently suppressed PDAC tumor growth and metastasis in PDAC mouse 
      models. PDAC cells with acquired resistance to MSK1/mTOR-inhibitors displayed 
      activated insulin-like growth factor 1 receptor (IGF1R) signaling and were 
      successfully eradicated by IGF1R inhibitor. Furthermore, MEK inhibitor trametinib 
      enhanced the efficacy of dual MSK1 and mTOR inhibition. Collectively, these 
      results identify therapeutic vulnerabilities of PDAC and an approach to overcome 
      acquired drug resistance to prolong therapeutic benefit.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Malvi, Parmanand
AU  - Malvi P
AD  - Department of Biochemistry and Molecular Genetics, University of Alabama at 
      Birmingham, Birmingham, AL 35233, USA.
FAU - Chava, Suresh
AU  - Chava S
AD  - Department of Biochemistry and Molecular Genetics, University of Alabama at 
      Birmingham, Birmingham, AL 35233, USA.
FAU - Cai, Guoping
AU  - Cai G
AD  - Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, 
      USA.
FAU - Hu, Kai
AU  - Hu K
AD  - Department of Molecular, Cell and Cancer Biology, University of Massachusetts 
      Medical School, Worcester, MA 01605, USA.
FAU - Zhu, Lihua Julie
AU  - Zhu LJ
AD  - Department of Molecular, Cell and Cancer Biology, University of Massachusetts 
      Medical School, Worcester, MA 01605, USA; Program in Molecular Medicine, 
      University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in 
      Bioinformatics and Integrative Biology, University of Massachusetts Medical 
      School, Worcester, MA 01605, USA.
FAU - Edwards, Yvonne J K
AU  - Edwards YJK
AD  - Department of Biochemistry and Molecular Genetics, University of Alabama at 
      Birmingham, Birmingham, AL 35233, USA.
FAU - Green, Michael R
AU  - Green MR
AD  - Department of Molecular, Cell and Cancer Biology, University of Massachusetts 
      Medical School, Worcester, MA 01605, USA.
FAU - Gupta, Romi
AU  - Gupta R
AD  - Department of Biochemistry and Molecular Genetics, University of Alabama at 
      Birmingham, Birmingham, AL 35233, USA; O'Neal Comprehensive Cancer Center, The 
      University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic 
      address: romigup@uab.edu.
FAU - Wajapeyee, Narendra
AU  - Wajapeyee N
AD  - Department of Biochemistry and Molecular Genetics, University of Alabama at 
      Birmingham, Birmingham, AL 35233, USA; O'Neal Comprehensive Cancer Center, The 
      University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic 
      address: nwajapey@uab.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231110
PL  - United States
TA  - Cell Rep Med
JT  - Cell reports. Medicine
JID - 101766894
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Neoplasm Proteins)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Cell Proliferation
MH  - *Pancreatic Neoplasms/drug therapy/genetics/metabolism
MH  - *Carcinoma, Pancreatic Ductal/drug therapy/genetics
MH  - TOR Serine-Threonine Kinases/pharmacology/therapeutic use
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Neoplasm Proteins
MH  - Mammals
PMC - PMC10694669
OTO - NOTNLM
OT  - HOXC6
OT  - MSK1 kinase
OT  - PDACs
OT  - PPP2R2B
OT  - metastasis
OT  - pancreatic cancer
OT  - protein phosphatase 2 regulatory subunit B beta
OT  - tumor growth
COIS- Declaration of interests All authors declare that they have no competing 
      interests.
EDAT- 2023/11/12 00:41
MHDA- 2023/11/27 12:44
PMCR- 2023/11/10
CRDT- 2023/11/11 18:41
PHST- 2023/02/09 00:00 [received]
PHST- 2023/10/13 00:00 [revised]
PHST- 2023/10/17 00:00 [accepted]
PHST- 2023/11/27 12:44 [medline]
PHST- 2023/11/12 00:41 [pubmed]
PHST- 2023/11/11 18:41 [entrez]
PHST- 2023/11/10 00:00 [pmc-release]
AID - S2666-3791(23)00479-2 [pii]
AID - 101285 [pii]
AID - 10.1016/j.xcrm.2023.101285 [doi]
PST - ppublish
SO  - Cell Rep Med. 2023 Nov 21;4(11):101285. doi: 10.1016/j.xcrm.2023.101285. Epub 
      2023 Nov 10.