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Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma
Published on: March 30, 2018
B-cell lymphoma-extra large is a promising drug target in Merkel cell carcinoma
Kaiji Fan1,2,3, Nalini Srinivas1,4, Linda Kubat1,2
1Department of Translational Skin Cancer Research, German Cancer Consortium %(DKTK%), Partner Site Essen, University Medicine Essen, Essen, Germany.
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.
Insights
This study identifies B-cell lymphoma extra-large (Bcl-xL) as a promising drug target for Merkel cell carcinoma (MCC). Inhibiting Bcl-xL, especially combined with PARP1 inhibition, shows significant anti-tumor effects in MCC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Merkel cell carcinoma (MCC) is an aggressive skin cancer.
- Current immunotherapies are insufficient for all advanced-stage MCC patients.
- Novel therapeutic targets are urgently needed for MCC.
Purpose of the Study:
- To identify overexpressed oncogenes as potential drug targets for MCC.
- To investigate the therapeutic potential of targeting Bcl-xL and PARP1 in MCC.
Main Methods:
- Copy number variations (CNVs) were analyzed using NanoString, ddPCR, and FISH.
- mRNA and protein expression of BCL2L1 (Bcl-xL) and PARP1 were quantified.
- Antitumor effects of Bcl-xL inhibitors and a PARP1 inhibitor were evaluated in vitro.
Main Results:
- BCL2L1 gains and amplifications were found in MCC cell lines and tumor tissues.
- BCL2L1 copy number gains correlated with increased Bcl-xL expression.
- Specific Bcl-xL inhibitors induced apoptosis in MCC cells.
- Combination therapy with Bcl-xL inhibitors and olaparib (PARP1 inhibitor) demonstrated synergistic antitumor effects.
Conclusions:
- Bcl-xL is highly expressed in MCC and represents an attractive therapeutic target.
- Targeting Bcl-xL, particularly in combination with PARP1 inhibition, offers a promising strategy for MCC treatment.
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