Molecular mechanism of secondary-resistant for trastuzumab in gastric cancer.

Abstract

58 Background: The ToGA trial demonstrated the significant efficacy of trastuzumab combined with chemotherapy in patients with HER2-positive GC. Although trastuzumab has become a key drug in cancer treatment, the resistance of breast cancer to trastuzumab is a major problem in clinical practice. The aim of this study was to identify molecular mechanism that regulates the sensitivity of HER2-positive GC cells to trastuzumab. Methods: (i) Establishment of trastuzumab-resistant GC cell: We cultured the HER2-positive cell line in the presence of trastuzumab (ii) microRNA array: We examined the miR expression profile in the parent and resistant cells using miR array analysis. (iii) Identification of novel miR-gene pathway: We focused on miR-223-FBXW7 pathway based on miRarray analysis. Results: (i) We established resistant cell without significant changes in HER2 or p-HER2 in the presence of trastuzumab continuously for 6 months. (IC 50: 0.17 vs. 988.8μg/ml) (ii) We identified 23 miRs up-regulated in the resistant cells as compared with the parental cells. Of these identified miR, 40% miRs are located on 19q13.42. (iii) the miR-223/FBXW7 pathway regulates the sensitivity of a HER2-positive gastric cancer cell line to trastuzumab through the modulation of apoptosis. Conclusions: This study suggested that the miR-223-FBXW7 pathway can be a crucial clue to the mechanism of resistance to trastuzumab in GC, leading to the development of individualized treatment in clinical practice.