Mechanisms of proteasome inhibitor action and resistance in cancer

David McConkey, Keyi Zhu

Research output: Contribution to journalArticle

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 2008
Externally publishedYes

Fingerprint

Proteasome Inhibitors
Neoplasms
Mantle-Cell Lymphoma
Aptitude
Proxy
Multiple Myeloma
Pancreatic Neoplasms
Drug Resistance
Proteins

Keywords

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

ASJC Scopus subject areas

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

Cite this

Mechanisms of proteasome inhibitor action and resistance in cancer. / McConkey, David; Zhu, Keyi.

In: Drug Resistance Updates, Vol. 11, No. 4-5, 08.2008, p. 164-179.

Research output: Contribution to journalArticle

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