梅毒细胞癌（MCC）是一种具有神经内分泌分化的侵袭性皮肤肿瘤。免疫疗法在治疗晚期MCC患者方面非常有效，但对于肿瘤无法被免疫系统控制的患者，急需寻找替代治疗方法。为了识别作为MCC潜在药物靶点的过度表达的癌基因。使用NanoString平台、数字微滴PCR（ddPCR）和FISH检测来确定拷贝数变异（CNV）；通过qRT-PCR确定BCL2L1和PARP1 mRNA表达水平，通过免疫印迹法检测Bcl-xl和PARP1蛋白。使用特定的Bcl-xL抑制剂和PARP1抑制剂单独或联合使用，以测试它们的抗肿瘤效果。筛选13个经典病毒阳性和阴性MCC细胞系的CNV，揭示了BCL2L1增益和扩增，在10个细胞系中通过ddPCR得到证实。通过ddPCR和FISH我们证明了BCL2L1增益已经存在于肿瘤组织中。BCL2L1拷贝数增益与Bcl-xL mRNA和蛋白表达的增加有关。然而，高Bcl-xL表达并不局限于携带BCL2L1增益/扩增的MCC细胞，这表明还存在其他表观遗传调节方式。Bcl-xL在MCC细胞中的功能相关性通过特定的Bcl-xL抑制剂（A1331852和WEHI-539）导致细胞凋亡得到了证明。由于MCC细胞系中PARP1的强烈表达和激活，我们接下来测试了Bcl-xL抑制剂与PARP1抑制剂奥拉帕尼的联合使用，它确实显示出协同的抗肿瘤效果。Bcl-xL在MCC中高表达，似乎是治疗这种肿瘤的一个有吸引力的治疗靶点；特别是由于Bcl-xL特定抑制剂的作用被同时PARP抑制剂协同增强。© 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.

Merkel cell carcinoma (MCC) is an aggressive skin tumor with neuroendocrine differentiation. Immunotherapies are very effective in the treatment of advanced stage MCC patients, but for patients whose tumor cannot be controlled by the immune system, alternative approaches are urgently needed.To identify overexpressed oncogenes as potential drug targets for MCC.NanoString platform, digital droplet PCR (ddPCR) and FISH assays were used to determine copy number variations (CNVs); BCL2L1 and PARP1 mRNA expression levels were determined by qRT-PCR, Bcl-xl and PARP1 protein by immunoblot. Specific Bcl-xL inhibitors and PARP1 inhibitor was used alone or in combination to test their antitumor effect.Screening for CNVs in 13 classic virus-positive and -negative MCC cell lines revealed BCL2L1 gains and amplifications, which were confirmed by ddPCR in 10 cell lines. By ddPCR and FISH we demonstrated that BCL2L1 gains are already present in tumor tissues. 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 harboring a BCL2L1 gain/amplification, suggesting additional epigenetic means 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. Due 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 indeed showed synergistic anti-tumour effects.Bcl-xL, which is highly expressed in MCC, appears to be an attractive therapeutic target for the treatment of this tumor; especially since the effect of specific Bcl-xL inhibitors is synergistically enhanced by simultaneous PARP inhibition.© 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.