Anti‑Axl monoclonal antibodies attenuate the migration of MDA‑MB‑231 breast cancer cells

Abstract

The receptor tyrosine kinase, anexelekto (Axl) is involved in tumor cell growth, migration and invasion, and has been associated with chemotherapy resistance, which makes it an attractive target for cancer therapy. In total, six Axl-targeted monoclonal antibodies (mAbs) and two antibody-drug conjugates have been reported in the last 10 years, which have been shown to have bioactivity in inhibiting tumor cell proliferation and migration. The Axl external cell domain (Axl -ECD ), consisting of 426 amino acids, has always been used as an antigen in the screening process for all six of these Axl-targeted mAbs. However, the Axl functional domain, which interacts with its natural ligand, growth arrest-specific protein 6 (Gas6), is only a small part of the Axl -ECD . Antibodies targeting the Axl functional domain may efficiently block Gas6-Axl binding and attenuate its downstream signals and activities. To the best of our knowledge, no mAbs targeting the Axl functional domain have been reported. In the present study, a major Axl functional domain interacting with Gas6 was determined using bioinformatics and structural biology methods. In MDA-MB-231 breast cancer cell assays, anti-Axl mAbs targeting this relatively specific Axl functional domain almost completely neutralized the stimulation of Gas6 in both Axl phosphorylation and cell migration assays, and showed similar activity to the positive control drug R428 (a small molecular tyrosine kinase inhibitor of Axl currently in phase II clinical trials) in the cell migration assay. Given the important role of Axl in tumor development and chemotherapy resistance, Axl-targeted mAbs could be used to inhibit tumor cells directly, as well as reduce the development of chemotherapy resistance by blocking Axl activity. The application of Axl-targeted mAbs combined with chemotherapy provides a promising treatment strategy for patients with tumors, particularly those with triple-negative breast cancer, for whom no targeted therapy is currently available.

Plumbagin has an inhibitory effect on the growth of TSCC PDX model and it enhances the anticancer efficacy of cisplatin

“…Anexelekto (AXL) is a member of the Tyro3, AXL, and Mertk family of receptor tyrosine kinases (RTKs). It is associated with tumor cell growth, migration, invasion, and immune suppression [47,[50][51][52]]. In addition, several studies reveal that secretogranin V (SCG5) is related to tumor prognosis [53,54].…”

Targeting Receptor Tyrosine Kinases as a Novel Strategy for the Treatment of Triple-Negative Breast Cancer

“… 131 Targeting AXL with mAbs blocked ligand-dependent receptor activation and TNBC cell migration and invasion. 138 , 140 Leconet et al showed that 20G7-D9, an anti-AXL mAb, inhibited tumor growth and bone metastasis in AXL-positive TNBC xenografts. 140 In an interesting report, Wei et al engineered T cells with a CAR consisting of a novel variable fragment against AXL and indicated its antigen-specific cytotoxicity in vitro and in vivo.…”

The profile of receptor protein tyrosine kinases (RPTKs): taking AXL and DDR as examples

“…Currently, there are several compounds in development targeting the Axl receptor, including small molecule inhibitors of AXL autophosphorylation and kinase activity [18], anti-AXL monoclonal antibodies [19], soluble receptors, nucleotide aptamers, and natural compounds [20].…”