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Title of Journal: Breast Cancer Res Treat

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Abbravation: Breast Cancer Research and Treatment

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Springer US

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DOI

10.1007/10501684_1434

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ISSN

1573-7217

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Rapamycin synergizes cisplatin sensitivity in basa

Authors: Su Wei Wong Kai Hung Tiong Weng Yip Kong Yuen Chee Yue Choon Hooi Chua Jae Ying Lim Chai Yuin Lee Sean I Quah Cindy Fow Cyril Chung Irene So Boon Shing Tan Heng Lungh Choo Rozita Rosli SoonKeng Cheong CheeOnn Leong
Publish Date: 2010/08/05
Volume: 128, Issue: 2, Pages: 301-313
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Abstract

Recent gene expression profiling studies have identified five breast cancer subtypes of which the basallike subtype is the most aggressive Basallike breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin its success is often compromised due to its doselimiting nephrotoxicity and the development of drug resistance To overcome this limitation our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies Using a validated kinase inhibitor library we showed that inhibition of the mTOR TGFβRI NFκB PI3K/AKT and MAPK pathways sensitized basallike MDAMB468 cells to cisplatin treatment Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basallike MDAMB468 MDAMB231 and HCC1937 cells but not in luminallike T47D or MCF7 cells We further showed that the synergistic effect of rapamycin plus cisplatin on basallike breast cancer cells was mediated through the induction of p73 Depletion of endogenous p73 in basallike cells abolished these synergistic effects In conclusion combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basallike breast cancersThis work was supported by a grant from the MAKNA Cancer Research Award Malaysia and eScience Fund 020209SF0010 from the Ministry of Science Technology and Innovation Malaysia to COL RR and SKC by the International Medical University IMU Research Fund to KHT BST and HLC and by the IMU BPharm Research Training Program to SWW WYK YCY CHC JYL CYL SIQ CF CC and IS No sponsors of this work had any role in the design or conduct of the study in the collection analysis and interpretation of the data or in the preparation review or approval of the manuscript

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