PMID- 34518309
OWN - NLM
STAT- MEDLINE
DCOM- 20220407
LR  - 20230504
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 27
IP  - 23
DP  - 2021 Dec 1
TI  - Single-Cell Profiling Reveals Metabolic Reprogramming as a Resistance Mechanism 
      in BRAF-Mutated Multiple Myeloma.
PG  - 6432-6444
LID - 10.1158/1078-0432.CCR-21-2040 [doi]
AB  - PURPOSE: Although remarkably effective in some patients, precision medicine 
      typically induces only transient responses despite initial absence of 
      resistance-conferring mutations. Using BRAF-mutated myeloma as a model for 
      resistance to precision medicine we investigated if BRAF-mutated cancer cells 
      have the ability to ensure their survival by rapidly adapting to BRAF inhibitor 
      treatment. EXPERIMENTAL DESIGN: Full-length single-cell RNA (scRNA) sequencing 
      (scRNA-seq) was conducted on 3 patients with BRAF-mutated myeloma and 1 healthy 
      donor. We sequenced 1,495 cells before, after 1 week, and at clinical relapse to 
      BRAF/MEK inhibitor treatment. We developed an in vitro model of dabrafenib 
      resistance using genetically homogeneous single-cell clones from two cell lines 
      with established BRAF mutations (U266, DP6). Transcriptional and epigenetic 
      adaptation in resistant cells were defined by RNA-seq and H3K27ac chromatin 
      immunoprecipitation sequencing (ChIP-seq). Mitochondrial metabolism was 
      characterized by metabolic flux analysis. RESULTS: Profiling by scRNA-seq 
      revealed rapid cellular state changes in response to BRAF/MEK inhibition in 
      patients with myeloma and cell lines. Transcriptional adaptation preceded 
      detectable outgrowth of genetically discernible drug-resistant clones and was 
      associated with widespread enhancer remodeling. As a dominant vulnerability, 
      dependency on oxidative phosphorylation (OxPhos) was induced. In treated 
      individuals, OxPhos was activated at the time of relapse and showed inverse 
      correlation to MAPK activation. Metabolic flux analysis confirmed OxPhos as a 
      preferential energetic resource of drug-persistent myeloma cells. CONCLUSIONS: 
      This study demonstrates that cancer cells have the ability to rapidly adapt to 
      precision treatments through transcriptional state changes, epigenetic 
      adaptation, and metabolic rewiring, thus facilitating the development of 
      refractory disease while simultaneously exposing novel vulnerabilities.
CI  - (c)2021 American Association for Cancer Research.
FAU - Waldschmidt, Johannes M
AU  - Waldschmidt JM
AUID- ORCID: 0000-0001-5340-1818
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
FAU - Kloeber, Jake A
AU  - Kloeber JA
AUID- ORCID: 0000-0002-6646-564X
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
FAU - Anand, Praveen
AU  - Anand P
AUID- ORCID: 0000-0002-2478-7042
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
FAU - Frede, Julia
AU  - Frede J
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
FAU - Kokkalis, Antonis
AU  - Kokkalis A
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
FAU - Dimitrova, Valeriya
AU  - Dimitrova V
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
FAU - Potdar, Sayalee
AU  - Potdar S
AUID- ORCID: 0000-0001-5390-1222
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
FAU - Nair, Monica S
AU  - Nair MS
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
FAU - Vijaykumar, Tushara
AU  - Vijaykumar T
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
FAU - Im, Nam Gyu
AU  - Im NG
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
FAU - Guillaumet-Adkins, Amy
AU  - Guillaumet-Adkins A
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
FAU - Chopra, Nitish
AU  - Chopra N
AUID- ORCID: 0000-0003-4535-7508
AD  - Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
FAU - Stuart, Hannah
AU  - Stuart H
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
FAU - Budano, Lillian
AU  - Budano L
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
FAU - Sotudeh, Noori
AU  - Sotudeh N
AUID- ORCID: 0000-0002-1683-7273
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
FAU - Guo, Guangwu
AU  - Guo G
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
FAU - Grassberger, Clemens
AU  - Grassberger C
AUID- ORCID: 0000-0002-4425-4489
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
FAU - Yee, Andrew J
AU  - Yee AJ
AUID- ORCID: 0000-0003-3623-7491
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
FAU - Laubach, Jacob P
AU  - Laubach JP
AUID- ORCID: 0000-0001-7565-2052
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma 
      Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      Massachusetts.
FAU - Richardson, Paul G
AU  - Richardson PG
AUID- ORCID: 0000-0002-7426-8865
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
FAU - Anderson, Kenneth C
AU  - Anderson KC
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma 
      Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      Massachusetts.
FAU - Raje, Noopur S
AU  - Raje NS
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
FAU - Knoechel, Birgit
AU  - Knoechel B
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts.
FAU - Lohr, Jens G
AU  - Lohr JG
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical 
      School, Boston, Massachusetts. jensg_lohr@dfci.harvard.edu.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
LA  - eng
GR  - K08 CA191026/CA/NCI NIH HHS/United States
GR  - K08 CA191091/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210913
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 (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  - Drug Resistance, Neoplasm
MH  - Humans
MH  - *Melanoma/drug therapy
MH  - *Multiple Myeloma/drug therapy/genetics
MH  - Mutation
MH  - Neoplasm Recurrence, Local/drug therapy
MH  - Protein Kinase Inhibitors/pharmacology/therapeutic use
MH  - Proto-Oncogene Proteins B-raf
MH  - Single-Cell Analysis
PMC - PMC8639639
MID - NIHMS1740893
EDAT- 2021/09/15 06:00
MHDA- 2022/04/08 06:00
PMCR- 2022/06/01
CRDT- 2021/09/14 05:55
PHST- 2021/06/05 00:00 [received]
PHST- 2021/08/04 00:00 [revised]
PHST- 2021/09/07 00:00 [accepted]
PHST- 2021/09/15 06:00 [pubmed]
PHST- 2022/04/08 06:00 [medline]
PHST- 2021/09/14 05:55 [entrez]
PHST- 2022/06/01 00:00 [pmc-release]
AID - 1078-0432.CCR-21-2040 [pii]
AID - 10.1158/1078-0432.CCR-21-2040 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2021 Dec 1;27(23):6432-6444. doi: 10.1158/1078-0432.CCR-21-2040. 
      Epub 2021 Sep 13.