PMID- 36991156
OWN - NLM
STAT- MEDLINE
DCOM- 20230710
LR  - 20231120
IS  - 1365-2133 (Electronic)
IS  - 0007-0963 (Linking)
VI  - 189
IP  - 1
DP  - 2023 Jul 7
TI  - B-cell lymphoma-extra large is a promising drug target in Merkel cell carcinoma.
PG  - 103-113
LID - 10.1093/bjd/ljad099 [doi]
AB  - BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin tumour with 
      neuroendocrine differentiation. Immunotherapies are effective in the treatment of 
      patients with advanced-stage MCC, but for patients whose tumours cannot be 
      controlled by the immune system, alternative approaches are urgently needed. 
      OBJECTIVES: To identify overexpressed oncogenes as potential drug targets for 
      MCC. METHODS: NanoString platform, digital droplet polymerase chain reaction 
      (ddPCR) and fluorescence in situ hybridization (FISH) assays were used to 
      determine copy number variations (CNVs); BCL2L1 and PARP1 mRNA expression levels 
      were determined by quantitative real-time polymerase chain reaction (qRT-PCR), 
      B-cell lymphoma extra-large (Bcl-xL) and poly (ADP-ribose) polymerase 1 (PARP1) 
      protein by immuno-blot. Specific Bcl-xL inhibitors and a PARP1 inhibitor were 
      used alone or in combination to test their antitumour effect. RESULTS: Screening 
      for CNVs in 13 classic Merkel cell polyomavirus (MCPyV)-positive and 
      MCPyV-negative MCC cell lines revealed BCL2L1 gains and amplifications, confirmed 
      by ddPCR in 10 cell lines. By ddPCR and FISH, we demonstrated that BCL2L1 gains 
      are present in tumour tissue. BCL2L1 copy number gains were associated with 
      increased Bcl-xL mRNA and protein expression. However, high Bcl-xL expression was 
      not restricted to MCC cells harbouring a BCL2L1 gain/amplification, suggesting 
      additional epigenetic means of regulation. The functional relevance of Bcl-xL in 
      MCC cells was demonstrated by the fact that specific Bcl-xL inhibitors (A1331852 
      and WEHI-539) led to the induction of apoptosis. Owing to the strong expression 
      and activation of PARP1 in MCC cell lines, we next tested the combination of 
      Bcl-xL inhibitors with the PARP1 inhibitor olaparib, which showed synergistic 
      antitumour effects. CONCLUSIONS: Bcl-xL, which is highly expressed in MCC, 
      appears to be an attractive therapeutic target for the treatment of this tumour, 
      especially as the effect of specific Bcl-xL inhibitors is synergistically 
      enhanced by simultaneous PARP inhibition.
CI  - (c) The Author(s) 2023. Published by Oxford University Press on behalf of British 
      Association of Dermatologists. All rights reserved. For permissions, please 
      e-mail: journals.permissions@oup.com.
FAU - Fan, Kaiji
AU  - Fan K
AUID- ORCID: 0000-0003-4310-4515
AD  - Department of Translational Skin Cancer Research, German Cancer Consortium 
      %(DKTK%), Partner Site Essen, University Medicine Essen, Essen, Germany.
AD  - Department of Dermatology, University Hospital Essen, Essen, Germany.
AD  - National Centre for Tumor Diseases WERA, Department of Internal Medicine III, 
      University Hospital Regensburg, Regensburg, Germany.
FAU - Srinivas, Nalini
AU  - Srinivas N
AUID- ORCID: 0000-0002-6899-0080
AD  - Department of Translational Skin Cancer Research, German Cancer Consortium 
      %(DKTK%), Partner Site Essen, University Medicine Essen, Essen, Germany.
AD  - German Cancer Research Center (DKFZ), Heidelberg, Germany.
FAU - Kubat, Linda
AU  - Kubat L
AUID- ORCID: 0000-0001-7046-2663
AD  - Department of Translational Skin Cancer Research, German Cancer Consortium 
      %(DKTK%), Partner Site Essen, University Medicine Essen, Essen, Germany.
AD  - Department of Dermatology, University Hospital Essen, Essen, Germany.
FAU - Gravemeyer, Jan
AU  - Gravemeyer J
AUID- ORCID: 0000-0003-4181-7685
AD  - Department of Translational Skin Cancer Research, German Cancer Consortium 
      %(DKTK%), Partner Site Essen, University Medicine Essen, Essen, Germany.
AD  - German Cancer Research Center (DKFZ), Heidelberg, Germany.
FAU - Sucker, Antje
AU  - Sucker A
AD  - Department of Dermatology, University Hospital Essen, Essen, Germany.
FAU - Schadendorf, Dirk
AU  - Schadendorf D
AUID- ORCID: 0000-0003-3524-7858
AD  - Department of Dermatology, University Hospital Essen, Essen, Germany.
AD  - German Cancer Research Center (DKFZ), Heidelberg, Germany.
FAU - Gambichler, Thilo
AU  - Gambichler T
AUID- ORCID: 0000-0001-7862-3695
AD  - Skin Cancer Center, Department of Dermatology, Ruhr-University Bochum, Bochum, 
      Germany.
FAU - Becker, Jurgen C
AU  - Becker JC
AUID- ORCID: 0000-0001-9183-653X
AD  - Department of Translational Skin Cancer Research, German Cancer Consortium 
      %(DKTK%), Partner Site Essen, University Medicine Essen, Essen, Germany.
AD  - Department of Dermatology, University Hospital Essen, Essen, Germany.
AD  - German Cancer Research Center (DKFZ), Heidelberg, Germany.
LA  - eng
PT  - Journal Article
PL  - England
TA  - Br J Dermatol
JT  - The British journal of dermatology
JID - 0004041
RN  - 0 (WEHI-539)
SB  - IM
CIN - Br J Dermatol. 2023 May 05;:. PMID: 37146163
CIN - Br J Dermatol. 2023 Jul 7;189(1):e33. PMID: 37418650
MH  - Humans
MH  - *Carcinoma, Merkel Cell/drug therapy/genetics
MH  - DNA Copy Number Variations
MH  - In Situ Hybridization, Fluorescence
MH  - *Skin Neoplasms/drug therapy/genetics/diagnosis
MH  - Real-Time Polymerase Chain Reaction
MH  - *Lymphoma, B-Cell/complications
MH  - *Merkel cell polyomavirus/genetics
MH  - *Polyomavirus Infections
COIS- Conflicts of interest D.S. reports partial financial support from Bristol Myers 
      Squibb for the conduct of this study and drug supply (nivolumab and ipilimumab) 
      support; grants (or contracts) from Amgen, Array/Pfizer, Bristol Myers Squibb, 
      MSD, Novartis and Roche; consulting fees from 4SC, Amgen, Array Biopharma, 
      AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Haystick, Immunocore, InFlarX, 
      Innocent, LabCorp, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, 
      Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron and 
      Sun Pharma; honoraria from Bristol Myers Squibb, MSD/Merck, Merck Serono, 
      Novartis, Roche, Sanofi and Sun Pharma; support for attending meetings or travel 
      support from Bristol Myers Squibb, MSD, Merck Serono, Novartis, Pierre Fabre and 
      Sanofi; participation on drug safety monitoring or advisory boards for 4SC, 
      Amgen, Array Biopharma, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, 
      Immunocore, InFlarX, Merck Serono, MSD, Nektar, NeraCare, Novartis, OncoSec, 
      Pfizer, Philogen, Pierre Fabre, Replimune, Roche, Sandoz, Sanofi/Regeneron and 
      SunPharma; leadership roles for DeCOG, the German Cancer Society, Hiege-Stiftung, 
      Deutsche Hautkrebsstiftung, NVKH e.V. and EuMelaReg. T.G. has received speakers 
      and/or advisory board honoraria from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, 
      Roche, AbbVie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre and Merck-Serono 
      outside the submitted work. J.C.B. receives speakers' bureau honoraria from 
      Amgen, Pfizer and Sanofi, and is a paid consultant/advisory board member for 
      Almirall, Merck Serono, Pfizer, 4SC, Recordati, InProTher and Sanofi. His group 
      receives research grants from IQVIA, Merck Serono and Alcedis. None of the 
      activities is related to the submitted work. The other authors declare they have 
      no conflicts of interest.
EDAT- 2023/03/30 06:00
MHDA- 2023/07/10 06:42
CRDT- 2023/03/29 23:22
PHST- 2022/08/24 00:00 [received]
PHST- 2023/01/23 00:00 [revised]
PHST- 2023/03/26 00:00 [accepted]
PHST- 2023/07/10 06:42 [medline]
PHST- 2023/03/30 06:00 [pubmed]
PHST- 2023/03/29 23:22 [entrez]
AID - 7093428 [pii]
AID - 10.1093/bjd/ljad099 [doi]
PST - ppublish
SO  - Br J Dermatol. 2023 Jul 7;189(1):103-113. doi: 10.1093/bjd/ljad099.