Mechanisms of resistance to rapamycins

Shile Huang, Peter J. Houghton

Research output: Contribution to journalReview articlepeer-review

130 Scopus citations


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 GI 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 FKBPI2 prevent rapamycin from binding to mTOR, conferring rapamycin resistance. Second, mutations or defects of mTOR-regulated proteins, including S6KI, 4E-BPI, PP2A-related phosphatases, and p27Kipl 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.

Original languageEnglish (US)
Pages (from-to)378-391
Number of pages14
JournalDrug Resistance Updates
Issue number6
StatePublished - 2001
Externally publishedYes


  • Drug resistance
  • MTOR
  • P27
  • Rapamycin
  • Signaling pathways

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)
  • Oncology
  • Cancer Research
  • Pharmacology


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