Synergistic Anti-Angiogenic Effect of Combined VEGFR Kinase Inhibitors, Lenvatinib, and Regorafenib: A Therapeutic Potential for Breast Cancer

Abstract

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.

Evaluation of the inhibitory effect of azoles on pharmacokinetics of lenvatinib in rats both in vivo and in vitro by UPLC‐MS/MS

“…Biological‐based models are available for the analysis and prediction of DDIs in the study of lenvatinib. In a study evaluating the therapeutic efficacy of lenvatinib in combination with regorafenib for breast cancer, it was shown that the combined administration of these drugs exhibited a synergistic effect on the survival of breast cancer cells, with observed variations in drug concentration 23 . Furthermore, the combination of lenvatinib and erlotibib, both VEGRF inhibitors, has been found to enhance the treatment of HCC by overcoming drug resistance 24 …”

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions

“…A clinical trial was conducted using PD-L1 with a multi kinase inhibitor in patients with MSS or pMMR CRC. Regorafenib targets stromal and oncogenic receptor tyrosine kinases, and shows anti-angiogenic activity due to its dual-target VEGFR2-TIE2 tyrosine kinase inhibition[ 143 ]. The NCT04126733 trial conducted between 2019 and 2022 included 94 CRC patients with MSS or pMMR[ 144 ].…”

Lnc-ZEB2-19 Inhibits the Progression and Lenvatinib Resistance of Hepatocellular Carcinoma by Attenuating the NF-κB Signaling Pathway through the TRA2A/RSPH14 Axis

“…Due to its insidious pathogenesis, approximately 70-80% of patients have developed late stages upon diagnosis, requiring targeted therapy [2][3][4]. Lenvatinib is one of the multi-target tyrosine kinase inhibitors (TKIs) targeting a collection of receptors primarily affecting angiogenesis [5,6]. Despite the notable survival benefits of lenvatinib in advanced HCC patients, lenvatinib resistance (LR) occurs throughout the entire process of targeted therapy and significantly compromises the prognosis of HCC patients [7].…”