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Mechanisms of resistance to rapamycins
1Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Abstract:
Rapamycins represent a novel family of anticancer agents, currently including rapamycin and its derivatives, CCI-779 and RAD001. Rapamycins inhibit the function of the mammalian target of rapamycin (mTOR), and potently suppress tumor cell growth by arresting cells in G1 phase or potentially inducing apoptosis of cells, in culture or in xenograft tumor models. However, recent data indicate that genetic mutations or compensatory changes in tumor cells influence the sensitivity of rapamycins. First, mutations of mTOR or FKBP12 prevent rapamycin from binding to mTOR, conferring rapamycin resistance. Second, mutations or defects of mTOR-regulated proteins, including S6K1, 4E-BP1, PP2A-related phosphatases, and p27(Kip1) also render rapamycin insensitivity. In addition, the status of ATM, p53, PTEN/Akt and 14-3-3 are also associated with rapamycin sensitivity. To better explore the role of rapamycins against tumors, this review will summarize the current knowledge of the mechanism of action of rapamycins, and progress in understanding mechanisms of acquired or intrinsic resistance.
Insights
Rapamycins, including mTOR inhibitors like CCI-779, fight cancer by halting tumor cell growth. However, genetic mutations can cause resistance to these vital anticancer agents.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Rapamycins are a class of anticancer agents targeting the mammalian target of rapamycin (mTOR).
- These drugs suppress tumor growth by cell cycle arrest or apoptosis.
- Tumor cell genetic alterations can impact rapamycin efficacy.
Purpose of the Study:
- To review the mechanism of action of rapamycins.
- To explore acquired and intrinsic resistance mechanisms.
- To summarize current knowledge on rapamycin sensitivity and resistance.
Main Methods:
- Literature review of rapamycin mechanism of action.
- Analysis of genetic factors influencing rapamycin sensitivity.
- Summary of research on mTOR pathway and related proteins.
Main Results:
- Rapamycins inhibit mTOR, suppressing tumor cell proliferation.
- Resistance arises from mutations in mTOR, FKBP12, or downstream effectors (S6K1, 4E-BP1, PP2A, p27).
- Tumor suppressor pathways (ATM, p53, PTEN/Akt) and 14-3-3 proteins also influence sensitivity.
Conclusions:
- Understanding resistance mechanisms is crucial for optimizing rapamycin therapy.
- Genetic profiling of tumors may predict response to rapamycin-based treatments.
- Further research is needed to overcome therapeutic resistance.