PMID- 31375515
OWN - NLM
STAT- MEDLINE
DCOM- 20200910
LR  - 20200910
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 25
IP  - 22
DP  - 2019 Nov 15
TI  - A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of 
      BRAF-mutated Melanoma to MAPK Inhibitors.
PG  - 6852-6867
LID - 10.1158/1078-0432.CCR-19-0253 [doi]
AB  - PURPOSE: Treatment of BRAF(V600E) -mutant melanomas with MAPK inhibitors (MAPKi) 
      results in significant tumor regression, but acquired resistance is pervasive. To 
      understand nonmutational mechanisms underlying the adaptation to MAPKi and to 
      identify novel vulnerabilities of melanomas treated with MAPKi, we focused on the 
      initial response phase during treatment with MAPKi. EXPERIMENTAL DESIGN: By 
      screening proteins expressed on the cell surface of melanoma cells, we identified 
      the fatty acid transporter CD36 as the most consistently upregulated protein upon 
      short-term treatment with MAPKi. We further investigated the effects of MAPKi on 
      fatty acid metabolism using in vitro and in vivo models and analyzing patients' 
      pre- and on-treatment tumor specimens. RESULTS: Melanoma cells treated with MAPKi 
      displayed increased levels of CD36 and of PPARalpha-mediated and carnitine 
      palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO). While CD36 
      is a useful marker of melanoma cells during adaptation and drug-tolerant phases, 
      the upregulation of CD36 is not functionally involved in FAO changes that 
      characterize MAPKi-treated cells. Increased FAO is required for BRAF(V600E) 
      -mutant melanoma cells to survive under the MAPKi-induced metabolic stress prior 
      to acquiring drug resistance. The upfront and concomitant inhibition of FAO, 
      glycolysis, and MAPK synergistically inhibits tumor cell growth in vitro and in 
      vivo. CONCLUSIONS: Thus, we identified a clinically relevant therapeutic approach 
      that has the potential to improve initial responses and to delay acquired drug 
      resistance of BRAF(V600E) -mutant melanoma.
CI  - (c)2019 American Association for Cancer Research.
FAU - Aloia, Andrea
AU  - Aloia A
AD  - Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland. 
      werner.kovacs@biol.ethz.ch aloia.andrea@libero.it.
FAU - Mullhaupt, Daniela
AU  - Mullhaupt D
AUID- ORCID: 0000-0003-4167-1591
AD  - Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
FAU - Chabbert, Christophe D
AU  - Chabbert CD
AUID- ORCID: 0000-0001-7851-4640
AD  - Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
FAU - Eberhart, Tanja
AU  - Eberhart T
AUID- ORCID: 0000-0002-3621-5594
AD  - Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
FAU - Fluckiger-Mangual, Stefanie
AU  - Fluckiger-Mangual S
AD  - Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
FAU - Vukolic, Ana
AU  - Vukolic A
AD  - Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
FAU - Eichhoff, Ossia
AU  - Eichhoff O
AUID- ORCID: 0000-0002-3319-1312
AD  - Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
FAU - Irmisch, Anja
AU  - Irmisch A
AD  - Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
FAU - Alexander, Leila T
AU  - Alexander LT
AD  - Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
FAU - Scibona, Ernesto
AU  - Scibona E
AUID- ORCID: 0000-0002-2012-5674
AD  - Institute of Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland.
FAU - Frederick, Dennie T
AU  - Frederick DT
AD  - Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
FAU - Miao, Benchun
AU  - Miao B
AD  - Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
FAU - Tian, Tian
AU  - Tian T
AD  - Department of Computer Science, New Jersey Institute of Technology, Newark, New 
      Jersey.
FAU - Cheng, Chaoran
AU  - Cheng C
AD  - Department of Computer Science, New Jersey Institute of Technology, Newark, New 
      Jersey.
FAU - Kwong, Lawrence N
AU  - Kwong LN
AD  - Department of Translational Molecular Pathology, The University of Texas MD 
      Anderson Cancer Center, Houston, Texas.
FAU - Wei, Zhi
AU  - Wei Z
AUID- ORCID: 0000-0001-6059-4267
AD  - Department of Computer Science, New Jersey Institute of Technology, Newark, New 
      Jersey.
FAU - Sullivan, Ryan J
AU  - Sullivan RJ
AD  - Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
FAU - Boland, Genevieve M
AU  - Boland GM
AUID- ORCID: 0000-0002-7522-6173
AD  - Department of Surgery, Massachusetts General Hospital Cancer Center, Boston, 
      Massachusetts.
FAU - Herlyn, Meenhard
AU  - Herlyn M
AD  - Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The 
      Wistar Institute, Philadelphia, Pennsylvania.
FAU - Flaherty, Keith T
AU  - Flaherty KT
AD  - Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
FAU - Zamboni, Nicola
AU  - Zamboni N
AD  - Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
FAU - Dummer, Reinhard
AU  - Dummer R
AD  - Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
FAU - Zhang, Gao
AU  - Zhang G
AD  - Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The 
      Wistar Institute, Philadelphia, Pennsylvania.
FAU - Levesque, Mitchell P
AU  - Levesque MP
AD  - Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
FAU - Krek, Wilhelm
AU  - Krek W
AD  - Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
FAU - Kovacs, Werner J
AU  - Kovacs WJ
AUID- ORCID: 0000-0002-4440-4344
AD  - Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland. 
      werner.kovacs@biol.ethz.ch aloia.andrea@libero.it.
LA  - eng
GR  - P01 CA114046/CA/NCI NIH HHS/United States
GR  - P30 CA010815/CA/NCI NIH HHS/United States
GR  - P50 CA174523/CA/NCI NIH HHS/United States
GR  - U54 CA224070/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190802
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Biomarkers)
RN  - 0 (CD36 Antigens)
RN  - 0 (Fatty Acids)
RN  - 0 (PPAR alpha)
RN  - 0 (PPARA protein, human)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
SB  - IM
MH  - *Adaptation, Biological
MH  - Alleles
MH  - Animals
MH  - Biomarkers
MH  - CD36 Antigens/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Disease Models, Animal
MH  - Drug Resistance, Neoplasm/genetics
MH  - Fatty Acids/*metabolism
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Genotype
MH  - Glycolysis
MH  - Humans
MH  - Immunophenotyping
MH  - Melanoma/*genetics/*metabolism/pathology
MH  - Mice
MH  - Models, Biological
MH  - *Mutation
MH  - Neoplasm Staging
MH  - *Oxidation-Reduction
MH  - PPAR alpha/metabolism
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins B-raf/*genetics
MH  - Xenograft Model Antitumor Assays
PMC - PMC6906212
MID - NIHMS1543208
COIS- DECLARATION OF INTEREST CDC is a full-time employee of Roche AG and a shareholder 
      in AstraZeneca. Other authors declare no competing interests.
EDAT- 2019/08/04 06:00
MHDA- 2020/09/12 06:00
PMCR- 2020/05/15
CRDT- 2019/08/04 06:00
PHST- 2019/01/21 00:00 [received]
PHST- 2019/05/23 00:00 [revised]
PHST- 2019/07/30 00:00 [accepted]
PHST- 2019/08/04 06:00 [pubmed]
PHST- 2020/09/12 06:00 [medline]
PHST- 2019/08/04 06:00 [entrez]
PHST- 2020/05/15 00:00 [pmc-release]
AID - 1078-0432.CCR-19-0253 [pii]
AID - 10.1158/1078-0432.CCR-19-0253 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2019 Nov 15;25(22):6852-6867. doi: 
      10.1158/1078-0432.CCR-19-0253. Epub 2019 Aug 2.