PMID- 34246984
OWN - NLM
STAT- MEDLINE
DCOM- 20220117
LR  - 20231213
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 23
IP  - 8
DP  - 2021 Aug
TI  - Plasma proteome alterations by MAPK inhibitors in BRAF(V600)-mutated metastatic 
      cutaneous melanoma.
PG  - 783-791
LID - S1476-5586(21)00042-7 [pii]
LID - 10.1016/j.neo.2021.06.002 [doi]
AB  - Approximately half of metastatic cutaneous melanomas (CM) harbor a mutation in 
      the BRAF protooncogene, upregulating the mitogen-activated protein kinase 
      (MAPK)-pathway. The development of inhibitors targeting the MAPK pathway (MAPKi), 
      i.e., BRAF- and MEK-inhibitors (BRAFi and MEKi), have substantially improved the 
      survival in BRAF(V600E/K)-mutated stage IV metastatic CM. However, most patients 
      develop resistance to treatment and no predictive biomarkers exist in practice. 
      This study aimed at discovering plasma proteome changes during treatment MAPKi in 
      patients with metastatic (stage IV) CM. Matched plasma samples before (pre) and 
      during treatment (trm) from 23 patients with stage IV CM, treated with 
      BRAF-inhibitors (BRAFi) alone or BRAF- and MEK- inhibitors combined (BRAFi and 
      MEKi), were collected and analyzed with targeted proteomics by proximity 
      extension assays. Additionally, plasma from 9 patients treated with BRAFi and 
      MEKi was analyzed with in-depth high-resolution isoelectric focusing 
      liquid-chromatography mass-spectrometry proteomics. Alterations of plasma 
      proteins involved in granzyme and interferon gamma pathways were detected in 
      patients treated with BRAFi, and cell adhesion-, neutrophil degranulation-, and 
      proteolysis pathways in patients treated with BRAFi and MEKi. Several proteins 
      were associated with progression-free survival after MAPKi treatment. We show 
      that the majority of the altered plasma proteins were traceable to 
      BRAF(V600E)-mutant metastatic CM tissue at mRNA level in 154 patients from the 
      TCGA, further strengthening their involvement in tumoral response to treatment. 
      This wide screen of plasma proteins unravels proteins that may serve as 
      predictive and/or prognostic biomarkers of MAPKi treatment, opening a window of 
      opportunity for plasma biomarker discovery in MAPKi-treatment of 
      BRAF(V600)-mutant metastatic CM.
CI  - Copyright (c) 2021. Published by Elsevier Inc.
FAU - Babacic, Haris
AU  - Babacic H
AD  - Department of Oncology-Pathology, Science for Life Laboratory, Karolinska 
      Institute, Stockholm, Sweden.
FAU - Eriksson, Hanna
AU  - Eriksson H
AD  - Theme Cancer / Department of Oncology, Karolinska University Hospital, Stockholm, 
      Sweden. Electronic address: hanna.eriksson.4@ki.se.
FAU - Pernemalm, Maria
AU  - Pernemalm M
AD  - Department of Oncology-Pathology, Science for Life Laboratory, Karolinska 
      Institute, Stockholm, Sweden.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210708
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (Blood Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proteome)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
SB  - IM
MH  - Adult
MH  - Aged
MH  - *Blood Proteins
MH  - Disease Management
MH  - Disease Susceptibility
MH  - Female
MH  - Humans
MH  - Male
MH  - Mass Spectrometry
MH  - Melanoma/*blood/diagnosis/drug therapy/*genetics
MH  - Middle Aged
MH  - *Mutation
MH  - Neoplasm Grading
MH  - Neoplasm Staging
MH  - Protein Kinase Inhibitors/pharmacology/therapeutic use
MH  - *Proteome
MH  - *Proteomics/methods
MH  - Proto-Oncogene Proteins B-raf/antagonists & inhibitors/*genetics
MH  - Skin Neoplasms/*blood/diagnosis/drug therapy/*genetics
MH  - Treatment Outcome
MH  - Melanoma, Cutaneous Malignant
PMC - PMC8274243
OTO - NOTNLM
OT  - BRAF and MEK inhibitors
OT  - Biomarkers
OT  - Melanoma
OT  - Mitogen-activated protein kinase
OT  - Plasma proteins
OT  - Targeted therapy
OT  - V600E mutation
EDAT- 2021/07/12 06:00
MHDA- 2022/01/18 06:00
PMCR- 2021/07/08
CRDT- 2021/07/11 20:48
PHST- 2021/02/22 00:00 [received]
PHST- 2021/06/01 00:00 [revised]
PHST- 2021/06/02 00:00 [accepted]
PHST- 2021/07/12 06:00 [pubmed]
PHST- 2022/01/18 06:00 [medline]
PHST- 2021/07/11 20:48 [entrez]
PHST- 2021/07/08 00:00 [pmc-release]
AID - S1476-5586(21)00042-7 [pii]
AID - 10.1016/j.neo.2021.06.002 [doi]
PST - ppublish
SO  - Neoplasia. 2021 Aug;23(8):783-791. doi: 10.1016/j.neo.2021.06.002. Epub 2021 Jul 
      8.