AXL Is a Logical Molecular Target in Head and Neck Squamous Cell Carcinoma

Abstract

Purpose Head and neck squamous cell carcinoma (HNSCC) represents the eighth most common malignancy worldwide. Standard of care treatments for HNSCC patients include surgery, radiation and chemotherapy. Additionally, the anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab is often used in combination with these treatment modalities. Despite clinical success with these therapeutics, HNSCC remains a difficult to treat malignancy. Thus, identification of new molecular targets is critical. Experimental Design In the current study, the receptor tyrosine kinase AXL was investigated as a molecular target in HNSCC using established cell lines, HNSCC patient derived xenografts (PDXs), and human tumors. HNSCC dependency on AXL was evaluated with both anti-AXL siRNAs and the small molecule AXL inhibitor R428. Furthermore, AXL inhibition was evaluated with standard of care treatment regimes used in HNSCC. Results AXL was found to be highly overexpressed in several models of HNSCC, where AXL was significantly associated with higher pathologic grade, presence of distant metastases and shorter relapse free survival in patients with HNSCC. Further investigations indicated that HNSCC cells were reliant on AXL for cellular proliferation, migration, and invasion. Additionally, targeting AXL increased HNSCC cell line sensitivity to chemotherapy, cetuximab, and radiation. Moreover, radiation resistant HNSCC cell line xenografts and PDXs expressed elevated levels of both total and activated AXL, indicating a role for AXL in radiation resistance. Conclusion Collectively, this study provides evidence for the role of AXL in HNSCC pathogenesis and supports further pre-clinical and clinical evaluation of anti-AXL therapeutics for the treatment of patients with HNSCC.

Axl Receptor Axis: A New Therapeutic Target in Lung Cancer

“…In head and neck squamous cell cancer, Axl inhibition decreases cancer cell proliferation, migration and invasion, and increases sensitivity to the anti-EGFR antibody cetuximab. 25 In a breast cancer model, sensitivity to taxanes increased 1,000-fold with coincident Axl inhibition. 26 Axl is also expressed on endothelial cells and plays a role in angiogenesis.…”

The Receptor Tyrosine Kinase AXL in Cancer Progression

“…Immunohistochemical analysis of primary tumors revealed that AXL expression correlates with metastasis and/or poor survival in patients with lung adenocarcinoma, glioblastoma multiforme, pancreatic, renal cell carcinoma, esophageal adenocarcinoma, oral squamous carcinoma, pleural mesothelioma, ovarian adenocarcinoma, colon cancer, head and neck squamous cell carcinoma, urothelial carcinoma, esophageal cell carcinoma, and hepatocellular carcinoma (Table 1, [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28]). Moreover, AXL expression correlates with drug resistance in patients with melanoma, myeloid leukemia, lung cancer, and renal cell carcinoma [29,30,31,32,33,34].…”

“…AXL overexpression within chemoresistant tumors promotes survival through the activation of the AKT and ERK1/2 signaling pathways and decreases apoptosis through the modulation of c-ABL [71]. In addition to chemotherapy, AXL also promotes resistance to conventional radiotherapy in head and neck cancers [22]. …”

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

“…Previous analysis indicated that UW-SCC1 was resistant to cetuximab therapy (24,25). Twelve mice were then injected with UWSCC-1 PDX in the flank and tumors were allowed grow to 200 mm 3 .…”