Abstract
AXL is a tyrosine kinase receptor activated by GAS6 and regulates cancer cell proliferation migration and angiogenesis. We studied AXL as new therapeutic target in colorectal cancer (CRC). Expression and activation of AXL and GAS6 were evaluated in a panel of human CRC cell lines. AXL gene silencing or pharmacologic inhibition with foretinib suppressed proliferation, migration and survival in CRC cells. In an orthotopic colon model of human HCT116 CRC cells overexpressing AXL, foretinib treatment caused significant inhibition of tumour growth and peritoneal metastatic spreading. AXL and GAS6 overexpression by immunohistochemistry (IHC) were found in 76,7% and 73.5%, respectively, of 223 human CRC specimens, correlating with less differentiated histological grading. GAS6 overexpression was associated with nodes involvement and tumour stage. AXL gene was found amplified by Fluorescence in situ hybridization (FISH) in 8/146 cases (5,4%) of CRC samples. Taken together, AXL inhibition could represent a novel therapeutic approach in CRC.
Highlights
Colorectal cancer (CRC) is a prominent global health problem, representing the third most common cancer worldwide [1]
Expression and activation of AXL in human colorectal cancer cell lines We first performed a screening with a receptor tyrosine kinase array in four human CRC cell lines (SW620, SW480, LOVO, HCT116) non-responsive to the anti-EGFR targeting drugs, as they harbour mutations in KRAS genes [18,19,20,21,22]
Among several receptors involved in CRC tumorigenesis, AXL phospho-protein was found in all four human CRC cell lines (Figure 1A)
Summary
Colorectal cancer (CRC) is a prominent global health problem, representing the third most common cancer worldwide [1]. Metastatic CRC (mCRC) occurs in about 25% of patients at diagnosis [2] and it is a not curable disease in approximately 25-30% of patients, following treatment of locoregional disease; several chemotherapeutics agents including irinotecan, oxaliplatin and more recently targeted monoclonal agents, such as cetuximab, panitumumab, bevacizumab and regorafenib contributed to extend the survival of these patients [3,4,5]. Resistance to both chemotherapy and molecular targeted agents might occur [6]. The primary ligand for TAM receptors is Growth ArrestSpecific 6 (GAS6), a fairly large (75 kDa), vitamin www.impactjournals.com/oncotarget
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
