Abstract 1849: A novel gene-pathway regulating of microRNA mediates resistance to trastuzumab forgastric cancer.

Abstract

Abstract Background: Recently, the efficacy of trastuzumab is indicated in patients with unresectable or recurrent HER2 positive gastric cancer from the results of ToGA trial, and trastuzumab administration was to be done in patients with gastric cancer. However, resistance to trastuzumab has become a problem in breast cancer. MicroRNAs (miRs) are involved in regulating multiple cellular pathways, including cell proliferation, differentiation, and chemotherapy resistance, and thus may function as oncogenes or tumor suppressing genes. The aim of current study is to clarify the miR-gene pathway regulating resistance to trastuzumab. Method: Using 6 gastric cancer cell lines, we examined the following items in vitro. 1. We examined the status of HER2 protein expression by western blotting. 2. We focused on miR-21 and its target gene PTEN and evaluated the expression of miR-21 and PTEN in HER2 positive gastric cancer cell lines by real time PCR and western blotting. 3. We examined the expression of PTEN and downstream gene to clary the target gene of miR-21 by over or down regulation of miR-21. 4. We investigated whether miR-21-PTEN pathway can affect the resistance of trastuzumab. Result: 1.We confirmed the status of HER2 in gastric cell lines. 2. The endogenous expression of PTEN and miR-21 showed inverse correlation in each cell lines. 3. The suppression of miR-21 increased PTEN expression with downregulation of P-Akt, persisting HER2 expression. 4. Overexpression of miR-21 can induce the resistance of trastuzumab, and suppression of miR-21 can restore the sensitivity of trastuzumab. Conclusion: Our current study revealed that miR-21-PTEN pathway can regulate the sensitivity of trastuzumab in HER2-positive gastric cancer cell lines. These findings suggest that this pathway can be crucial clue to the mechanism of resistance to trastuzumab in gastric cancer. To elucidate the mechanism of resistance to trastuzumab can lead to the development of individualized treatment. Citation Format: Kojiro Eto, Masayuki Watanabe, Masaaki Iwatsuki, Hideo Baba. A novel gene-pathway regulating of microRNA mediates resistance to trastuzumab forgastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1849. doi:10.1158/1538-7445.AM2013-1849