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

Pinar Kanlikilicer, Bulent Ozpolat, Burcu Aslan, Recep Bayraktar, Nilgun Gurbuz, Cristian Rodriguez-Aguayo, Emine Bayraktar, Merve Denizli, Vianey Gonzalez-Villasana, Cristina Ivan, Ganesh L.R. Lokesh, Paola Amero, Silvia Catuogno, Monika Haemmerle, Sherry Yen Yao Wu, Rahul Mitra, David G. Gorenstein, David E. Volk, Vittorio de Franciscis, Anil K. SoodGabriel Lopez-Berestein

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)251-262
Number of pages12
JournalMolecular Therapy - Nucleic Acids
Volume9
DOIs
StatePublished - Dec 2017

Keywords

  • aptamer
  • AXL
  • metastasis
  • ovarian cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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