Abstract
HER2-positive advanced gastric cancer patients frequently develop resistance to trastuzumab through mechanisms still poorly understood. In breast cancer, other members of the HER-family are known to be involved in trastuzumab-resistance, as is overexpression of the scaffold protein IQGAP1. In the present work, we investigated acquired resistance to trastuzumab in gastric cancer experimental models. Trastuzumab-resistant (HR) subclones derived from 3 HER2-overexpressing gastric cancer cells were generated and characterized for alterations in HER2-signaling mechanisms by next-generation sequencing, immunohistochemical, western blot and qRT-PCR techniques, and molecular modeling analysis. All subclones showed a reduced growth rate with respect to parental cell lines but each had a different resistance mechanism. In NCI N87 HR cells, characterized by a marked increase in HER2-signaling pathways with respect to the parental cell line, trastuzumab sensitivity was restored when IQGAP1 expression was silenced. AKG HR subclone showed higher HER3 protein expression than the parental line. High nuclear HER4 levels were observed in KKP HR cells. In conclusion, our study revealed that high IQGAP1 expression leads to resistance to trastuzumab in gastric cancer. Furthermore, 2 new mutations of the HER2 gene that may be involved in acquired resistance were identified in AKG HR and KKP HR subclones.
Highlights
Gastric cancer is the fourth most common malignant disease and the second leading cause of cancer-related death worldwide [1]
human epidermal growth factor receptor 2 (HER2) was highly expressed in NCI N87 with a diffuse plasma membrane and cytosolic staining pattern
HER3 was expressed in KKP and AKG cells, albeit to a lesser degree (~40% and ~30% of positive cells, respectively), whereas its staining pattern was mainly restricted to the cytosol
Summary
Gastric cancer is the fourth most common malignant disease and the second leading cause of cancer-related death worldwide [1]. In 2010, the phase III ToGA trial showed the superiority of trastuzumab plus chemotherapy (based on a cisplatinwww.impactjournals.com/oncotarget fluoropyrimidine doublet) in patients with HER2-positive metastatic gastric cancer over chemotherapy alone in terms of response rate, progression-free survival (PFS) and overall survival (OS) [14]. These results led to the approval of trastuzumab as the first molecular targeted therapy for gastric cancer. The efficacy of HER2-targeted agents has proven more limited and unsatisfactory than originally expected because the majority of patients with gastric cancer develop acquire resistance to treatment [16]. The identification of mechanisms underlying treatment resistance would enhance the benefit from HER2-targeted therapy in patients with HER2-positive gastric cancer
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