Mechanisms of proteasome inhibitor action and resistance in cancer

Research output: Contribution to journalArticlepeer-review

Abstract

Proteasome inhibitors (PIs), such as bortezomib, carfilzomib or NPI-0052, have excellent clinical activity in patients with multiple myeloma and mantle cell lymphoma, and they are currently being evaluated in combination with other agents in patients with solid tumors. Although they exert broad effects on cancer cells, their ability to (1) stabilize pro-apoptotic members of the BCL-2 family, (2) inhibit the two major pathways leading to NFκB activation, and (3) cause the build-up of misfolded proteins appear to be particularly important. In addition, PIs may disrupt tumor-stromal interactions that drive NFκB activation and angiogenesis and in such a way sensitize cancer cells to other agents. Still, drug resistance ultimately emerges in all tumors that initially respond to PIs. This review provides an overview of the current thinking about how PIs may kill cancer cells exemplified for pancreatic cancer and the possible mechanisms involved in resistance to PIs.

Original languageEnglish (US)
Pages (from-to)164-179
Number of pages16
JournalDrug Resistance Updates
Volume11
Issue number4-5
DOIs
StatePublished - Aug 1 2008
Externally publishedYes

Keywords

  • Autophagy
  • BIP
  • Bcl2 family
  • Grp78
  • NFκB
  • Pancreas
  • Pancreatic cancer
  • Unfolded protein response (UPR)
  • elf2α
  • p53

ASJC Scopus subject areas

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

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