The AXL receptor tyrosine kinase is associated with adverse prognosis and distant metastasis in esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is a frequently recurrent deadly cancer for which no efficient targeted drug exists. AXL is an adverse prognostic factor in some cancers. Strong clinical evidence to support the prognostic role of AXL in ESCC is lacking. A total of 116 patients diagnosed with operable primary ESCC were enrolled. Both AXL and HER2 expression were detected by immunohistochemistry (IHC) in esophageal tissue and were correlated with the clinical outcome of patients. The efficacy of the AXL targeted drug foretinib was also evaluated in ESCC cells. Expression of AXL was found in about 80 % of ESCC tissue, and was significantly correlated with progression of tumor (P<0.001), increased risk of death (Hazard ratio HR [95 % CI=2.09[1.09-4.04], P=0.028], and distant metastasis (odds ratio OR [95 %CI]=3.96 (1.16-13.60), P=0.029). The adverse clinical impact of AXL was more evident when cumulatively expressed with HER2. In cell model, ESCC cells were more sensitive to AXL inhibitor foretinib than to the HER2 inhibitor lapatinib. Meanwhile, the AXL inhibitor foretinib showed a synergistic effect with HER2 inhibitors and the potential to overcome drug resistance to lapatinib. We thus concluded that AXL is a strong adverse prognostic factor for ESCC. Therapeutic agents targeting AXL have great potential to improve prognosis of ESCC patients.

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].…”

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

“…In most of these cases, aberrant overexpression of TAM receptors is observed; mutations in TAM receptors are an exception [19]. Mechanistically, TAM receptor signaling supports several key cellular events in the tumor, from cell growth and survival, to metastasis, epithelial-mesenchymal transition (EMT), and resistance to chemotherapy [20,22,23,24,122,123,124,125]. Importantly, experimental evidence demonstrates that TAM antagonism can efficiently revert these processes [22,126,127,128,129,130], underscoring the potential benefits of TAM inhibition for cancer therapy (Figure 3).…”

Translational research in thoracic surgery—the National Taiwan University Hospital experience

“…We recently demonstrated that patients positive for AXL in tumor tissue have increased risks of death and distant metastasis, and their median survival time dramatically decreased from about 47 to 14 months. We also found that the unfavorable clinical effect of AXL was more marked when cumulatively expressed with HER2 RTK (21). In the cell model, ESCC cells were relatively sensitive to the AXL inhibitor foretinib compared to HER2 inhibitors and that foretinib exhibited a synergistic effect with HER2 inhibitors (21).…”

“…We also found that the unfavorable clinical effect of AXL was more marked when cumulatively expressed with HER2 RTK (21). In the cell model, ESCC cells were relatively sensitive to the AXL inhibitor foretinib compared to HER2 inhibitors and that foretinib exhibited a synergistic effect with HER2 inhibitors (21). Therefore, we suggested therapeutic drugs targeting AXL as a potential approach to developing targeted therapy for ESCC.…”