PMID- 36343387
OWN - NLM
STAT- MEDLINE
DCOM- 20230106
LR  - 20230209
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 22
IP  - 1
DP  - 2023 Jan 3
TI  - Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic 
      Rheostat to Trigger Colorectal Cancer Cell Death.
PG  - 52-62
LID - 10.1158/1535-7163.MCT-22-0101 [doi]
AB  - The EGFR/RAS/MEK/ERK signaling pathway (ERK/MAPK) is hyperactivated in most 
      colorectal cancers. A current limitation of inhibitors of this pathway is that 
      they primarily induce cytostatic effects in colorectal cancer cells. 
      Nevertheless, these drugs do induce expression of proapoptotic factors, 
      suggesting they may prime colorectal cancer cells to undergo apoptosis. As 
      histone deacetylase inhibitors (HDACis) induce expression of multiple 
      proapoptotic proteins, we examined whether they could synergize with ERK/MAPK 
      inhibitors to trigger colorectal cancer cell apoptosis. Combined MEK/ERK and HDAC 
      inhibition synergistically induced apoptosis in colorectal cancer cell lines and 
      patient-derived tumor organoids in vitro, and attenuated Apc-initiated adenoma 
      formation in vivo. Mechanistically, combined MAPK/HDAC inhibition enhanced 
      expression of the BH3-only proapoptotic proteins BIM and BMF, and their knockdown 
      significantly attenuated MAPK/HDAC inhibitor-induced apoptosis. Importantly, we 
      demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce 
      apoptosis can be tailored to specific MAPK genotypes in colorectal cancers, by 
      combining an HDAC inhibitor with either an EGFR, KRASG12C or BRAFV600 inhibitor 
      in KRAS/BRAFWT; KRASG12C, BRAFV600E colorectal cancer cell lines, respectively. 
      These findings identify a series of ERK/MAPK genotype-tailored treatment 
      strategies that can readily undergo clinical testing for the treatment of 
      colorectal cancer.
CI  - (c)2022 The Authors; Published by the American Association for Cancer Research.
FAU - Jenkins, Laura J
AU  - Jenkins LJ
AUID- ORCID: 0000-0001-9218-8669
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
FAU - Luk, Ian Y
AU  - Luk IY
AUID- ORCID: 0000-0001-7229-0543
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
FAU - Fairlie, W Douglas
AU  - Fairlie WD
AUID- ORCID: 0000-0002-2498-1160
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
AD  - Department of Biochemistry and Genetics, La Trobe Institute for Molecular 
      Science, La Trobe University, Melbourne, Victoria, Australia.
FAU - Lee, Erinna F
AU  - Lee EF
AUID- ORCID: 0000-0003-1255-9808
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
AD  - Department of Biochemistry and Genetics, La Trobe Institute for Molecular 
      Science, La Trobe University, Melbourne, Victoria, Australia.
FAU - Palmieri, Michelle
AU  - Palmieri M
AUID- ORCID: 0000-0003-3379-9974
AD  - Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical 
      Research, Melbourne, Victoria, Australia.
FAU - Schoffer, Kael L
AU  - Schoffer KL
AUID- ORCID: 0000-0002-5683-9935
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
FAU - Tan, Tao
AU  - Tan T
AUID- ORCID: 0000-0001-5924-4112
AD  - Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical 
      Research, Melbourne, Victoria, Australia.
FAU - Ng, Irvin
AU  - Ng I
AUID- ORCID: 0000-0002-1357-4666
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
FAU - Vukelic, Natalia
AU  - Vukelic N
AUID- ORCID: 0000-0003-0123-5701
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
FAU - Tran, Sharon
AU  - Tran S
AUID- ORCID: 0000-0003-1321-5556
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
FAU - Tse, Janson W T
AU  - Tse JWT
AUID- ORCID: 0000-0002-4592-1220
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
FAU - Nightingale, Rebecca
AU  - Nightingale R
AUID- ORCID: 0000-0003-3251-4113
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
FAU - Alam, Zakia
AU  - Alam Z
AUID- ORCID: 0000-0002-9426-4538
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
FAU - Chionh, Fiona
AU  - Chionh F
AUID- ORCID: 0000-0002-9392-5816
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
FAU - Iatropoulos, George
AU  - Iatropoulos G
AUID- ORCID: 0000-0002-7000-5806
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
FAU - Ernst, Matthias
AU  - Ernst M
AUID- ORCID: 0000-0002-6399-1177
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
FAU - Afshar-Sterle, Shoukat
AU  - Afshar-Sterle S
AUID- ORCID: 0000-0003-2678-7297
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
FAU - Desai, Jayesh
AU  - Desai J
AUID- ORCID: 0000-0003-4246-9344
AD  - Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
FAU - Gibbs, Peter
AU  - Gibbs P
AUID- ORCID: 0000-0003-1423-4484
AD  - Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical 
      Research, Melbourne, Victoria, Australia.
FAU - Sieber, Oliver M
AU  - Sieber OM
AUID- ORCID: 0000-0001-9480-0786
AD  - Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical 
      Research, Melbourne, Victoria, Australia.
AD  - Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, 
      Australia.
AD  - Department of Surgery, The University of Melbourne, Melbourne, Victoria, 
      Australia.
AD  - Department of Biochemistry and Molecular Biology, Monash University, Melbourne, 
      Victoria, Australia.
FAU - Dhillon, Amardeep S
AU  - Dhillon AS
AUID- ORCID: 0000-0002-6065-663X
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - The Institute for Mental and Physical Health and Clinical Translation, School of 
      Medicine, Deakin University, Geelong, Australia.
FAU - Tebbutt, Niall C
AU  - Tebbutt NC
AUID- ORCID: 0000-0003-2613-5168
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
AD  - Department of Surgery, The University of Melbourne, Melbourne, Victoria, 
      Australia.
FAU - Mariadason, John M
AU  - Mariadason JM
AUID- ORCID: 0000-0001-9123-7684
AD  - Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia.
AD  - School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Humans
MH  - Apoptosis
MH  - Apoptosis Regulatory Proteins
MH  - Cell Death
MH  - Cell Line, Tumor
MH  - *Colorectal Neoplasms/drug therapy/genetics/metabolism
MH  - ErbB Receptors
MH  - *Histone Deacetylase Inhibitors/pharmacology
MH  - Mitogen-Activated Protein Kinase Kinases
MH  - MAP Kinase Signaling System
PMC - PMC9808369
EDAT- 2022/11/08 06:00
MHDA- 2023/01/05 06:00
PMCR- 2023/01/03
CRDT- 2022/11/07 18:03
PHST- 2022/02/10 00:00 [received]
PHST- 2022/07/21 00:00 [revised]
PHST- 2022/10/31 00:00 [accepted]
PHST- 2022/11/08 06:00 [pubmed]
PHST- 2023/01/05 06:00 [medline]
PHST- 2022/11/07 18:03 [entrez]
PHST- 2023/01/03 00:00 [pmc-release]
AID - 711987 [pii]
AID - MCT-22-0101 [pii]
AID - 10.1158/1535-7163.MCT-22-0101 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2023 Jan 3;22(1):52-62. doi: 10.1158/1535-7163.MCT-22-0101.