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., Competing Interests: 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., (© 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.)