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THE STUDY OF DRUG RESISTANCE TO MTOR INHIBITION

by
Tzung-Ju Wu
M.S. National Yang-Ming University, 2005

Thesis Advisors: X.F. Steven Zheng, Ph.D.
Graduate Program in Cellular & Molecular Pharmacology

RWJMS Research Tower Building
Seminar Room, 4th Floor
Piscataway, NJ

Thursday, September 11, 2014
10:00 a.m.


Abstract

The mammalian target of rapamycin (mTOR) is the central regulator of cell growth, metabolism and survival by integrating upstream stimuli to orchestrate downstream growth-related biological processes. The mTOR-signaling pathway is commonly dysregulated in different types of human cancers and has been regarded as an attractive anti-cancer drug target. However, the first generation of mTOR inhibitors, rapamycin and its analogs (rapalogs) has only shown clinical success in a few subsets of cancers and the overall efficacy of rapalogs as monotherapies is limited. The second generation of mTOR inhibitors, which is the ATP competitive inhibitors, has been developed recently to improve the clinical efficacy of mTOR-targeting therapy. In this dissertation, we established an in vitro model of acquired rapamycin-resistant (ARR) breast cancer cells to examine the effect of mTOR catalytic inhibitors to rapamycin-resistant cancer cells. We found that mTOR catalytic inhibitors acutely overcome the resistance of ARR breast cancer cells. This study demonstrates the therapeutic potential of mTOR catalytic inhibitors targeted to rapamycin-refractory cancer cell types.
One of the prevailing mechanisms of drug-resistance to ATP-competitive kinase inhibitors is the emergence of resistant mutations. As mTOR catalytic inhibitors are currently in phase I/II clinical evaluation, we hypothesize that drug-resistant mutation will develop in these therapies targeted to mTOR. We developed a yeast-based screen and identified potential drug-resistant mutations against a diverse panel of mTOR catalytic inhibitors. Several loss-of-function mutations have also been mapped in the screen, which provided advanced information for future studies of mTOR kinase activity and mTOR-targeted therapeutics.


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