https://scholars.lib.ntu.edu.tw/handle/123456789/328735
標題: | Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency | 作者: | KENG-HSUEH LAN | 公開日期: | 2007 | 卷: | 13 | 期: | 19 | 起(迄)頁: | 5883-5888 | 來源出版物: | Clinical Cancer Research | 摘要: | Purpose: We have previously shown that PTEN loss confers trastuzumab resistance in ErbB2-overexpressing breast cancer using cell culture, xenograft models, and patient samples. This is a critical clinical problem because trastuzumab is usedi n a variety of therapeutic regimens, and at the current time, there are no established clinical strategies to overcome trastuzumab resistance. Here, we did preclinical studies on the efficacy of clinically applicable inhibitors of the Akt/mammalian target of rapamycin (mTOR) pathway to restore trastuzumab sensitivity to PTEN-deficient cells. Experimental Design: Cell culture and xenograft models were used to test a panel of clinically applicable, small-molecule inhibitors of the Akt/mTOR signal transduction pathway, a critical pathway downstream of ErbB2, and identify compounds with the ability to restore trastuzumab sensitivity to PTEN-deficient cells. Results: When trastuzumab was combined with the Akt inhibitor triciribine, breast cancer cell growth was inhibited and apoptosis was induced. In a xenograft model, combination therapy with trastuzumab andtr iciribine dramatically inhibited tumor growth. The combination of trastuzumab and the mTOR inhibitor RAD001 also slowed breast cancer cell growth in vitro and in vivo. Conclusions: Combining trastuzumab with inhibitors of the Akt/mTOR pathway is a clinically applicable strategy and combinations of trastuzumab with triciribine or RAD001 are promising regimens for rescue of trastuzumab resistance caused by PTEN loss. ? 2007 American Association for Cancer Research. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-35348917266&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/328735 |
DOI: | 10.1158/1078-0432.CCR-06-2837 | SDG/關鍵字: | antisense oligodeoxynucleotide; dimethyl sulfoxide; edelfosine; epidermal growth factor receptor 2; everolimus; integrin linked kinase; mammalian target of rapamycin inhibitor; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; protein kinase B inhibitor; trastuzumab; triciribine; animal experiment; animal model; apoptosis; article; breast cancer; cancer cell; cancer inhibition; cell culture; combination chemotherapy; controlled study; drug inhibition; drug potentiation; female; human; human cell; in vitro study; in vivo study; monotherapy; mouse; nonhuman; priority journal; signal transduction; Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bromodeoxyuridine; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Mice; Mice, SCID; Neoplasm Transplantation; Neoplasms; PTEN Phosphohydrolase; Ribonucleosides; Sirolimus |
顯示於: | 腫瘤醫學研究所 |
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