Esophageal
adenocarcinoma (EAC) is characterized by resistance to
chemotherapy and poor outcome. Although
cisplatin (CDDP) has been used as a first-line
therapy in patients with EAC, resistance remains a major clinical problem. The
AXL receptor tyrosine kinase, originally isolated as a transforming gene from
leukemia, is overexpressed in several solid
tumors. Herein, we assessed AXL
protein expression in human EACs and examined its role in CDDP resistance in human EAC cells. AXL overexpression was detected in more than 50% of
tumors examined. Elevating AXL in nonoverexpressing cells doubled the CDDP IC(50) and increased cell survival three-fold, while attenuating AXL in overexpressing cells reduced survival two-fold. The effects of AXL modulation on cell survival were associated with changes in cellular and molecular markers of apoptosis. Mechanistic investigations revealed that AXL blocked CDDP-induced activation of endogenous p73β (TP73), reducing its
protein half-life, and inhibited CDDP-induced levels of p-c-ABL(Y412) and p-p73β(Y99). These changes were associated with a disruption of c-ABL/p73β
protein interactions due to association with c-ABL in the cytoplasm, thereby blocking nuclear accumulation of c-ABL and phosphorylation of p73β in response to DNA damage. Together, our results establish that AXL promotes CDDP resistance in esophageal
adenocarcinoma and argue that therapeutic targeting of AXL may sensitize these
cancers to
DNA-damaging drugs.