Abstract 1444: Sensitivity to trastuzumab for gastric cancer is regulated by miR-223/FBXW7 pathway

Abstract

Abstract Background: A recent large-scale phase III study (the ToGA trial) demonstrated the significant efficacy of trastuzumab in addition to chemotherapy in patients with HER2-positive gastric cancer (GC). Although trastuzumab has become a key drug in recent cancer treatment, resistance to trastuzumab for breast cancer is a major problem in clinical practice. However, it is unclear whether similar mechanisms of trastuzumab resistance act in GC. F-box and WD repeat domain-containing 7 (FBXW7) is the substrate recognition components of an evolutionarily conserved SCF (complex of SKP1, CUL1, and F-box protein)-type ubiquitin ligase complexe, which has been well characterized and shown to have important roles in regulating the stability of multiple oncoprotein substrates, including cyclin E, c-Myc, Notch, c-Jun, mTOR, and MCL1. Therefore, FBXW7 is recognized to be one of the major causes of drug resistance. The aim of the current study is to clarify the novel microRNA (miR)-FBXW7 pathway regulating resistance to trastuzumab. Method: Using 5 GC cell lines, we examined the following items in vitro. 1. We examined the status of FBXW7 expression by quantitative real-time reverse transcription-PCR (qRT-PCR). 2. We established the trastuzumab resistance GC cell line with continuous trastuzumab administration. Parent GC cell line and resistance GC cell line are subjected to miR PCR array. 3. We focused on miR223-FBXW7 pathway. We examined the status of HER2, miR223, FBXW7, and its target gene MCL1 expression by up or down regulation of miR-223 in GC cell lines. 4. We investigated whether the miR-223-FBXW7 pathway can affect the resistance of trastuzumab. Result: FBXW7 and miR-223 expression showed inverse correlation. Moreover, miR-223 expression was increased and FBXW7 expression was decreased whereas MCL1 expression, downstream targets of FBXW7, was increased while no significant change was observed both in HER2 and p-HER2 in GC trastuzumab resistance cells. Overexpression of miR-223 decreased FBXW7 expression persisting HER2 and p-HER2 expression and can induce the resistance of trastuzumab. The suppression of miR-223 increased FBXW7 expression persisting HER2 and p-HER2 expression and can simultaneously restore the sensitivity of trastuzumab.Conclusion: Our current study revealed for the first time that regulated the sensitivity of HER2-positive GC cell line to trastuzumab. These findings suggest that this pathway may be crucial to the mechanism of resistance to trastuzumab in GC, which may lead to the development of individualized treatment in clinical practice. Citation Format: Kojiro Eto, Masaaki Iwatsuki, Takatsugu Ishimoto, Hideo Baba. Sensitivity to trastuzumab for gastric cancer is regulated by miR-223/FBXW7 pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1444. doi:10.1158/1538-7445.AM2014-1444