PMID- 30660770
OWN - NLM
STAT- MEDLINE
DCOM- 20200528
LR  - 20200528
IS  - 1876-7737 (Electronic)
IS  - 1874-3919 (Linking)
VI  - 195
DP  - 2019 Mar 20
TI  - A large scale proteome analysis of the gefitinib primary resistance overcome by 
      KDAC inhibition in KRAS mutated adenocarcinoma cells overexpressing amphiregulin.
PG  - 114-124
LID - S1874-3919(19)30017-X [pii]
LID - 10.1016/j.jprot.2019.01.009 [doi]
AB  - KDAC inhibitors (KDACi) overcome gefitinib primary resistance in non-small cell 
      lung cancer (NSCLC) including mutant-KRAS lung adenocarcinoma. To identify which 
      proteins are involved in the restoration of this sensitivity and to provide new 
      therapeutic targets for mutant-KRAS lung adenocarcinoma, we performed an iTRAQ 
      quantitative proteomic analysis after subcellular fractionation of H358-NSCLC 
      treated with gefitinib and KDACi (TSA/NAM) versus gefitinib alone. The 86 
      proteins found to have been significantly dysregulated between the two 
      conditions, were mainly involved in cellular metabolism and cell transcription 
      processes. As expected, the pathway related to histone modifications was affected 
      by the KDACi. Pathways known for controlling tumor development and 
      (chemo)-resistance (miRNA biogenesis/glutathione metabolism) were affected by the 
      KDACi/gefitinib treatment. Moreover, 57 dysregulated proteins were upstream of 
      apoptosis (such as eEF1A2 and STAT1) and hence provide potential therapeutic 
      targets. The inhibition by siRNA of eEF1A2 expression resulted in a slight 
      decrease in H358-NSCLC viability. In addition, eEF1A2 and STAT1 siRNA 
      transfections suggested that both STAT1 and eEF1A2 prevent AKT phosphorylation 
      known for enhancing gefitinib resistance in NSCLC. Therefore, altogether our data 
      provide new insights into proteome regulations in the context of overcoming the 
      NSCLC resistance to gefitinib through KDACi in H358 KRAS mutated and 
      amphiregulin-overexpressing NSCLC cells.
CI  - Copyright (c) 2019 Elsevier B.V. All rights reserved.
FAU - Lehmann, Sylvia G
AU  - Lehmann SG
AD  - Univ. Grenoble Alpes, LBFA and BEeSy, PROMETHEE Proteomic Platform, Grenoble, 
      France; Inserm, U1055, PROMETHEE Proteomic Platform, Grenoble, France; CHU 
      Grenoble Alpes, Institut de Biologie et de Pathologie, PROMETHEE Proteomic 
      Platform, Grenoble, France; Univ. Grenoble Alpes, ISTerre, F-38000 Grenoble, 
      France.
FAU - Seve, Michel
AU  - Seve M
AD  - Univ. Grenoble Alpes, LBFA and BEeSy, PROMETHEE Proteomic Platform, Grenoble, 
      France; Inserm, U1055, PROMETHEE Proteomic Platform, Grenoble, France; CHU 
      Grenoble Alpes, Institut de Biologie et de Pathologie, PROMETHEE Proteomic 
      Platform, Grenoble, France.
FAU - Vanwonterghem, Laetitia
AU  - Vanwonterghem L
AD  - Cancer target and experimental therapeutics, Institute for Advanced Biosciences, 
      INSERM U1209, CNRS UMR5301, Univ. Grenoble Alpes, F-38000 Grenoble, France.
FAU - Michelland, Sylvie
AU  - Michelland S
AD  - Univ. Grenoble Alpes, LBFA and BEeSy, PROMETHEE Proteomic Platform, Grenoble, 
      France; Inserm, U1055, PROMETHEE Proteomic Platform, Grenoble, France; CHU 
      Grenoble Alpes, Institut de Biologie et de Pathologie, PROMETHEE Proteomic 
      Platform, Grenoble, France.
FAU - Cunin, Valerie
AU  - Cunin V
AD  - Univ. Grenoble Alpes, LBFA and BEeSy, PROMETHEE Proteomic Platform, Grenoble, 
      France; Inserm, U1055, PROMETHEE Proteomic Platform, Grenoble, France; CHU 
      Grenoble Alpes, Institut de Biologie et de Pathologie, PROMETHEE Proteomic 
      Platform, Grenoble, France.
FAU - Coll, Jean-Luc
AU  - Coll JL
AD  - Cancer target and experimental therapeutics, Institute for Advanced Biosciences, 
      INSERM U1209, CNRS UMR5301, Univ. Grenoble Alpes, F-38000 Grenoble, France.
FAU - Hurbin, Amandine
AU  - Hurbin A
AD  - Cancer target and experimental therapeutics, Institute for Advanced Biosciences, 
      INSERM U1209, CNRS UMR5301, Univ. Grenoble Alpes, F-38000 Grenoble, France. 
      Electronic address: amandine.hurbin@univ-grenoble-alpes.fr.
FAU - Bourgoin-Voillard, Sandrine
AU  - Bourgoin-Voillard S
AD  - Univ. Grenoble Alpes, LBFA and BEeSy, PROMETHEE Proteomic Platform, Grenoble, 
      France; Inserm, U1055, PROMETHEE Proteomic Platform, Grenoble, France; CHU 
      Grenoble Alpes, Institut de Biologie et de Pathologie, PROMETHEE Proteomic 
      Platform, Grenoble, France. Electronic address: 
      sandrine.bourgoin@univ-grenoble-alpes.fr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190117
PL  - Netherlands
TA  - J Proteomics
JT  - Journal of proteomics
JID - 101475056
RN  - 0 (KRAS protein, human)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Adenocarcinoma of Lung/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/*drug effects/genetics
MH  - Gefitinib/*pharmacology
MH  - Gene Expression Regulation, Neoplastic/*drug effects
MH  - Humans
MH  - Lung Neoplasms/genetics/*metabolism
MH  - *Mutation
MH  - *Proteomics
MH  - Proto-Oncogene Proteins p21(ras)/genetics/*metabolism
OTO - NOTNLM
OT  - EGFR-TKI
OT  - Gefitinib
OT  - Inhibitors of lysine deacetylases
OT  - Non-small cell lung cancer
OT  - Quantitative proteomics
OT  - Resistance
EDAT- 2019/01/21 06:00
MHDA- 2020/05/29 06:00
CRDT- 2019/01/21 06:00
PHST- 2018/12/05 00:00 [received]
PHST- 2019/01/14 00:00 [accepted]
PHST- 2019/01/21 06:00 [pubmed]
PHST- 2020/05/29 06:00 [medline]
PHST- 2019/01/21 06:00 [entrez]
AID - S1874-3919(19)30017-X [pii]
AID - 10.1016/j.jprot.2019.01.009 [doi]
PST - ppublish
SO  - J Proteomics. 2019 Mar 20;195:114-124. doi: 10.1016/j.jprot.2019.01.009. Epub 
      2019 Jan 17.