Targeting AXL and the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Melanoma

• Published in: Molecular cancer therapeutics Vol. 19; no. 3; pp. 895 - 905
• Main Authors: Flem-Karlsen, Karine, McFadden, Erin, Omar, Nasrin, Haugen, Mads H, Øy, Geir Frode, Ryder, Truls, Gullestad, Hans Petter, Hermann, Robert, Mælandsmo, Gunhild Mari, Flørenes, Vivi Ann
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.03.2020
• Subjects: Animals; Apoptosis; Basale medisinske, odontologiske og veterinærmedisinske fag: 710; Basic medical, dental and veterinary science disciplines: 710; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Cycle Checkpoints; Cell Proliferation; Checkpoint Kinase 1 - antagonists & inhibitors; Checkpoint Kinase 2 - antagonists & inhibitors; DNA Damage; DNA Repair; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Gene Expression Regulation, Neoplastic; Humans; Lymphatic Metastasis; Medical disciplines: 700; Medisinske Fag: 700; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; Mice; Mice, Nude; Neoplasm Invasiveness; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; RNA, Small Interfering - genetics; Thiophenes - pharmacology; Tumor Cells, Cultured; Urea - analogs & derivatives; Urea - pharmacology; VDP; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-19-0290

Receptor tyrosine kinase AXL is found upregulated in various types of cancer, including melanoma, and correlates with an aggressive cancer phenotype, inducing cell proliferation and epithelial-to-mesenchymal transition. In addition, AXL has recently been linked to chemotherapy resistance, and inhibition of AXL is found to increase DNA damage and reduce expression of DNA repair proteins. In light of this, we aimed to investigate whether targeting AXL together with DNA damage response proteins would be therapeutically beneficial. Using melanoma cell lines, we observed that combined reduction of AXL and CHK1/CHK2 signaling decreased proliferation, deregulated cell-cycle progression, increased apoptosis, and reduced expression of DNA damage response proteins. Enhanced therapeutic effect of combined treatment, as compared with mono-treatment, was further observed in a patient-derived xenograft model and, of particular interest, when applying a three-dimensional spheroid drug sensitivity assay on tumor cells harvested directly from 27 patients with melanoma lymph node metastases. Together, these results indicate that targeting AXL together with the DNA damage response pathway could be a promising treatment strategy in melanoma, and that further investigations in patient groups lacking treatment alternatives should be pursued.