B-cell lymphoma extra-large (Bcl-xL) is a promising drug target in Merkel cell carcinoma

Abstract

Abstract Background 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. Objective To identify overexpressed oncogenes as potential drug targets for MCC. Methods 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. Results 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. Conclusions 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.