Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models

Abstract

Despite substantial improvements in the treatment strategies, ovarian cancer is still the most lethal gynecological malignancy. Identification of drug treatable therapeutic targets and their safe and effective targeting is critical to improve patient survival in ovarian cancer. AXL receptor tyrosine kinase (RTK) has been proposed to be an important therapeutic target for metastatic and advanced-stage human ovarian cancer. We found that AXL-RTK expression is associated with significantly shorter patient survival based on the The Cancer Genome Atlas patient database. To target AXL-RTK, we developed a chemically modified serum nuclease-stable AXL aptamer (AXL-APTAMER), and we evaluated its in vitro and in vivo antitumor activity using in vitro assays as well as two intraperitoneal animal models. AXL-aptamer treatment inhibited the phosphorylation and the activity of AXL, impaired the migration and invasion ability of ovarian cancer cells, and led to the inhibition of tumor growth and number of intraperitoneal metastatic nodules, which was associated with the inhibition of AXL activity and angiogenesis in tumors. When combined with paclitaxel, in vivo systemic (intravenous [i.v.]) administration of AXL-aptamer treatment markedly enhanced the antitumor efficacy of paclitaxel in mice. Taken together, our data indicate that AXL-aptamers successfully target in vivo AXL-RTK and inhibit its AXL activity and tumor growth and progression, representing a promising strategy for the treatment of ovarian cancer.

Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer

“…AXL is expressed in high-grade ovarian cancers, and AXL overexpression is correlated with poor clinical outcomes. Additionally, in both ovarian cancer and other solid cancers, inhibiting AXL prevents migration and invasion in vitro and in mouse models (3,(6)(7)(8).…”

“…Further, AXL was one of several genes found to be amplified in ovarian cancer cells conditioned in platinum (15,16). Corno and colleagues demonstrate no significant impact of AXL inhibition on platinum sensitivity in the IGROV-Pt1 cell line (17), while Kanlikilicer and colleagues report a novel AXL inhibitor improves response to paclitaxel, but only in an intraperitoneal mouse model and without mechanistic investigation (8). However, no work has yet addressed whether or not AXL expression contributes to ovarian cancer resistance to the standard-of-care treatments paclitaxel and carboplatin and a mechanism by which this occurs.…”

Clinical and Histopathological Parameters Correlate with Microvessel Density but Not with Vascular Endothelial Growth Factor Expression in Ovarian Cancer

“…Also, both PDGFR-beta and VEGFR-2 may become novel predictive biomarkers for therapy resistance and for overall and progression-free sur vival [23]. Moreover, despite the benefits on antiangiogenic therapy, a complex and properly defined therapeutic management in ovarian cancers may also include AXL receptor tyrosine kinase (AXL-RTK) inhibitors that detain a certified role in suppressing tumor growth and progression [24].…”

Aptamer‐Engineered Natural Killer Cells for Cell‐Specific Adaptive Immunotherapy

“…Aptamers are a group of short, single‐stranded oligonucleotides with unique 3D structures . Similar to protein antibodies, aptamers specifically recognize their targets, which can include nucleic acids, proteins, cells, and even tissue, with high affinity . Aptamers are considered “chemical antibodies,” given that they are chemically synthesized and have the ability to specifically bind their targets through 3D recognition .…”