Combined effects of cytokine TRAIL-based DR5-specific fusion protein with olaparib on tumor cell lines with different BRCA mutation status

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Abstract

Tumor cell death induction via activation of TRAIL (tumor necrosis factor-related apoptosis inducing ligand) cytokine signaling pathway is a promising strategy for anticancer therapy. Previously, we developed a fusion protein SRH-DR5-B-iRGD based on the DR5 (death receptor 5)-specific cytokine TRAIL variant DR5-B with antiangiogenic peptides. The SRH peptide specifically binds to the VEGFR2 (vascular endothelial growth factor receptor 2) receptor and blocks its VEGF-mediated activation; the iRGD peptide binds to integrin αvβ3 and the NRP-1 (neuropilin-1) receptor. All of these targets are known to be overexpressed on the surface of tumor cells. In the current study, we investigated the cytotoxic activity of the SRH-DR5-B-iRGD fusion protein in comparison with DR5-B in vitro in ovarian and breast adenocarcinoma cell lines with different BRCA mutation status in combination with a targeted poly(ADP-ribose) polymerase (PARP) inhibitor olaparib. Olaparib synergistically enhanced the cytotoxicity of TRAIL-based proteins regardless of the presence of BRCA mutations in the cells, and this effect was more pronounced for SRH-DR5-B-iRGD. Thus, the combination of SRH-DR5-B-iRGD with olaparib can be considered as a new approach to treatment of ovarian and breast adenocarcinomas regardless of the presence of BRCA mutations.

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About the authors

A. V. Yagolovich

Lomonosov Moscow State University

Author for correspondence.
Email: yagolovichav@my.msu.ru

Faculty of Biology

Russian Federation, Leninskie Gory 1/12, Moscow, 119234

A. A. Isakova

Lomonosov Moscow State University; Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Email: yagolovichav@my.msu.ru

Faculty of Biology

Russian Federation, Leninskie Gory 1/12, Moscow, 119234; ul. Miklukho-Maklaya 16/10, Moscow, 117997

E. V. Kukovyakina

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Email: yagolovichav@my.msu.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

D. A. Dolgikh

Lomonosov Moscow State University; Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Email: yagolovichav@my.msu.ru

Faculty of Biology

Russian Federation, Leninskie Gory 1/12, Moscow, 119234; ul. Miklukho-Maklaya 16/10, Moscow, 117997

M. P. Kirpichnikov

Lomonosov Moscow State University; Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Email: yagolovichav@my.msu.ru

Faculty of Biology

Russian Federation, Leninskie Gory 1/12, Moscow, 119234; ul. Miklukho-Maklaya 16/10, Moscow, 117997

M. E. Gasparian

Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Email: yagolovichav@my.msu.ru
Russian Federation, ul. Miklukho-Maklaya 16/10, Moscow, 117997

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Supplementary files

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2. Fig. 1. Comparison of the expression of genes encoding TRAIL (TNFSF10), VEGFA (VEGFA) ligands and DR5 (TNFRSF10B), VEGFR2 (KDR), integrin αvβ3 (ITGA2B) and NRP1 (NRP1) receptors: (a) – in ovarian cancer (OC) samples and normal samples, averaged over all normal tissues of the body, using the Mann–Whitney U-test; (b, c – comparison of paired samples of tumor (OC) and locally located adjacent normal tissues using the paired Wilcoxon statistical test.

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3. Fig. 2. Comparison of the expression of genes encoding TRAIL (TNFSF10), VEGFA (VEGFA) ligands and DR5 (TNFRSF10B), VEGFR2 (KDR), integrin αvβ3 (ITGA2B) and NRP1 (NRP1) receptors: (a) – in breast cancer (BC) samples and normal samples, averaged over all normal tissues of the body, using the Mann–Whitney U-test; (b, c – comparison of paired samples of tumor (BC) and locally located adjacent normal tissues using the paired Wilcoxon statistical test.

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4. Fig. 3. Correlation of the expression of the BRCA1 and BRCA2 genes with the expression of the TNFRSF10B (a), KDR (b), ITGA2B (c) and NRP1 (g) genes in OC tumor samples according to RNA sequencing data, studied using the TNMplot online tool (https://tnmplot.com/analysis/).

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5. Fig. 4. Correlation of the expression of the BRCA1 and BRCA2 genes with the expression of the TNFRSF10B (a), KDR (b), ITGA2B (c) and NRP1 (g) genes in breast cancer tumor samples according to RNA sequencing data, studied using the TNMplot online tool (https://tnmplot.com/analysis/).

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6. Fig. 5. Cytotoxic activity of olaparib in combination with DR5-B or SRH-DR5-B-iRGD ligands (toxic concentration 5 nM). A2780, OVCAR3, UWB1.289 (OC) or MDA-MB-436 (BC) cells were incubated for 48 h and viability was analyzed using the MTT assay.

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7. Fig. 6. Cytotoxic activity of DR5-B and SRH-DR5-B-iRGD ligands in combination with olaparib (toxic concentration 20 μM for OVCAR3, UWB1.289 and A2780 cells and 1 μM for MDA-MB-436). A2780, OVCAR3, UWB1.289 (OC) or MDA-MB-436 (BC) cells were incubated for 48 h and viability was analyzed using the MTT assay.

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