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Multi-Omics Analysis of the Anti-tumor Synergistic Mechanism and Potential Application of Immune Checkpoint Blockade Combined With Lenvatinib.

ABSTRACT: The combination of immune-checkpoint blockade (ICB) and lenvatinib has demonstrated robust clinical effects that are superior to those of monotherapies, but the synergistic anti-tumor mechanisms remain unclear. Exploring the synergistic molecular mechanisms and early identifying potential application have key importance for clinical therapeutics. We firstly systematically reviewed published data of ICB in combination with lenvatinib for the treatment of cancer by meta-analysis. A subsequent bioinformatics analysis explored the mechanism of combined ICB and lenvatinib therapy in 33 cancer types. Transcriptomic analysis was conducted by RNA-seq, and genomic analysis was performed on gene mutations and copy-number alteration data. Tumor-related pathways and tumor immune micro-environment (TIME) were also investigated. The meta-analysis showed a 38.0% objective response rate (ORR) and 79% disease control rate (DCR) for ICB combined with lenvatinib. Multi-omics analysis revealed that ICB and lenvatinib target genes were highly expressed and showed driving alterations in six specific malignancies. Pathway-enrichment analysis found target genes were implicated in tumor development, angiogenesis, and immunoregulatory associated pathways. This study verified the potential synergistic mechanisms of ICB combined with lenvatinib at transcriptomics, genomics, protein, and cellular levels and recognized nine tumor types had ≥ 2 positive treatment-related molecular characteristics, which might benefit particularly from this combined strategy. The findings would help to provide clinical insights and theoretical basis for optimizing of targeted therapy-immunotherapy combinations, and for guiding individualized precision-medicine approaches for cancer treatment.

SUBMITTER: Lu Y

PROVIDER: S-EPMC8458708 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Breast cancer currently affects more than two million women worldwide, and its incidence is steadily increasing. One of the most essential factors of invasion and metastasis of breast cancer cells is angiogenesis and non-angiogenic vascularization. Lenvatinib and Regorafenib share the same anti-angiogenic effect by inhibiting vascular endothelial growth factor receptors (VEGFRs subtypes 1 to 3) and have been approved for treating different types of cancer. Methods: We investigated Lenvatinib and Regorafenib effects on a well-established in-vitro model of breast cancer using MCF-7 (estrogen, progesterone receptor-positive, and HER2-negative), MDA-MB-231 (triple negative), as well as Human Umbilical Vascular Endothelial Cell line (HUVEC) cell lines. We performed the cell viability assay on four groups of cells, which included a control group, a Lenvatinib treated only group, a Regorafenib treated only group, and a group treated with a combination of both drugs at 24, 48, and 72 h. Data were analyzed as means ± standard deviation, and the drug−drug interactions with Compusyn software. Cellular migration assay, tube formation assay, and Western blots were conducted to determine the functional and the protein expression of downstream signals such as Caspase-9, anti-apoptotic Survivin, P-ERK, and total-ERK in the control and treatment groups. Results: MCF-7 cells showed a reduction in cell survival rates with higher dosing and longer incubation periods with each drug and with the combination of drugs. A synergistic interaction was identified (CI < 1) with both drugs on MCF7 at different dose combinations and at a higher dose in MDA-MB-231 cells. Furthermore, there was a marked decrease in the anti-angiogenic effect of both drugs in tube formation assay using MDA-MB-231 cells and survivin protein expression in MCF-7, and those antitumor markers showed a better outcome in drug combination than the use of each drug alone. Conclusion: Our result is the first to report the synergistic anti-angiogenic potential of combination therapy of Lenvatinib and Regorafenib. Therefore, it shows their therapeutic potential in breast cancer, including the aggressive types. Further studies are warranted to confirm and explore this therapeutic approach.

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Multi-Omics Analysis of the Anti-tumor Synergistic Mechanism and Potential Application of Immune Checkpoint Blockade Combined With Lenvatinib.

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