Abstract
AXL receptor tyrosine kinase is overexpressed in esophageal adenocarcinoma (EAC) and several other types of malignancies; hence, it may be a valuable therapeutic target. Herein, we investigated the role of AXL in regulating c‐MYC expression and resistance to the chemotherapeutic agent epirubicin in EAC. Using in vitro EAC cell models, we found that AXL overexpression enhances epirubicin resistance in sensitive cells. Conversely, genetic knockdown or pharmacological inhibition of AXL sensitizes resistant cells to epirubicin. Notably, we showed that inhibition or knockdown of c‐MYC markedly sensitizes AXL‐dependent resistant cells to epirubicin, and our data demonstrated that AXL promotes epirubicin resistance through transcriptional upregulation of c‐MYC. We showed that AXL overexpression significantly increased transcriptional activity, mRNA, and protein levels of c‐MYC. Conversely, AXL knockdown reversed these effects. Mechanistic investigations indicated that AXL upregulates c‐MYC expression through activation of the AKT/β‐catenin signaling pathway. Data from a tumor xenograft mouse model indicated that inhibition of AXL with R428 in combination with epirubicin synergistically suppresses tumor growth and proliferation. Our results demonstrate that AXL promotes epirubicin resistance through transcriptional upregulation of c‐MYC in EAC. Our findings support future clinical trials to assess the therapeutic potential of R428 in epirubicin‐resistant tumors with overexpression of AXL and activation of c‐MYC.
Highlights
The incidence rates of esophageal adenocarcinoma (EAC) have been increasing at epidemic proportions in the Western world over the recent decades, reflecting increases in gastroesophageal reflux disease (GERD) and Barrett’s esophagus, a precancerous lesion
We have previously reported that AXL plays an important role in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cisplatin resistance in EAC cells (Hong and Belkhiri, 2013; Hong et al, 2013)
We investigated whether high AXL expression correlated with resistance to epirubicin in EAC cell lines
Summary
The incidence rates of esophageal adenocarcinoma (EAC) have been increasing at epidemic proportions in the Western world over the recent decades, reflecting increases in gastroesophageal reflux disease (GERD) and Barrett’s esophagus, a precancerous lesion. These risk factors have been related primarily to obesity, poor diet, and the absence of Helicobacter pylori infection The treatment options for EAC includes surgical resection, radiotherapy, and chemotherapy (Ku and Ilson, 2009). The prognosis of this malignancy remains very poor as the overall 5-year survival rate of EAC patients is below 20% The prognosis of this malignancy remains very poor as the overall 5-year survival rate of EAC patients is below 20% (reviewed in Ref. Ilson, 2008)
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