Abstract
Human epidermal growth factor receptor 2 (HER2) targeted therapy is currently considered as the standard treatment for HER2-positive advanced gastric cancer (GC). However, unsatisfactory results of recent phase III clinical trials involving lapatinib suggested biomarkers for selection of patients. The aim of this study was to identify JWA as a biomarker for lapatinib resistance in GC cells and elucidate the underlying mechanisms. Lapatinib was effective to the intrinsic cisplatin-resistant GC cells. JWA activation conferred lapatinib unresponsiveness, but reversed cisplatin resistance in GC cells. Whereas, deletion of JWA significantly restored lapatinib suppression on proliferation and lapatinib-induced apoptosis. JWA-induced down-regulation of HER2 and activation of ERK phosphorylation led to lapatinib resistance. Furthermore, c-Cbl represented a novel mechanism for HER2 degradation enhanced by JWA in GC cells. Taken together, JWA is a potential predictive marker for lapatinib resistance, targeting the patients that may benefit from lapatinib treatment in human GC.
Highlights
Gastric cancer (GC) is one of the most common malignant cancers and the third most common cause of cancer-related death worldwide [1]
We demonstrated for the first time that JWA can be a biomarker for lapatinib and reported a novel pathway how JWA regulates Human epidermal growth factor receptor 2 (HER2) in gastric cancer (GC) cells
We have provided new evidences supporting that degradation of HER2 and phosphorylation of ERK induced by JWA can be the factors for lapatinib resistance in GC
Summary
Gastric cancer (GC) is one of the most common malignant cancers and the third most common cause of cancer-related death worldwide [1]. Overexpression of HER2 has been reported to be associated with poor prognosis in several human cancers, such as breast cancer and GC [2, 3]. HER2 targeted therapy has aroused great interest in the treatment of advanced GC [4]. Trastuzumab and lapatinib have been approved for the treatment of patients with advanced HER2 positive breast cancer [5,6,7]. In heterogeneous advanced GC, lapatinib has not been widely acknowledged for clinical treatment so far. A serious of lapatinib-concerned clinical trials in advanced GC have been undergoing with great attentions [8,9,10]. The disappointing results of the negative phase III TyTAN and LOGiC trials have been reported recently [9, 10].
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