Title:Updated Review and Perspective on 20S Proteasome Inhibitors in the Treatment of Lung Cancer
Volume: 20
Issue: 6
Author(s): Sagar O. Rohondia*, Zainab Sabry Othman Ahmed and Q. Ping Dou*
Affiliation:
- Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, Wayne State University School of Medicine, 4100 John R, Detroit, MI,United States
- Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, Wayne State University School of Medicine, 4100 John R, Detroit, MI,United States
Keywords:
Lung cancer, NSCLC, SCLC, ubiquitin proteasome system, proteasome inhibitors, bortezomib.
Abstract:
Lung cancer is the leading cause of cancer-related deaths worldwide. Most lung cancer
patients are diagnosed at advanced stages and may benefit from pembrolizumab (anti-PD-1 antibody),
cytotoxic chemotherapy and other adjuvant therapies. Despite the availability of various therapies,
the response and survival rates have been low. Therefore, the study of different targets for the
treatment of lung cancer has been one of the major focuses of cancer research.
The ubiquitin proteasome system (UPS) is a crucial regulator of cell homeostasis and plays an essential
role in the growth and development of all cells. The UPS is dysregulated in human cancer cells including
lung cancer cells. Therefore, targeting UPS is potentially a selective, effective treatment for lung
cancer. Bortezomib, a 20S proteasome inhibitor that is clinically approved for the management of multiple
myeloma, has been studied in various preclinical and clinical models of lung cancer.
Most preclinical studies have shown that a 20S proteasome inhibitor alone and its combination with
other chemotherapeutic agents induce apoptosis in non-small cell lung cancer cell lines and animal
models. Owing to the impressive preclinical results, many clinical trials were initiated using 20S
proteasome inhibitors either as monotherapy or in combination with other conventional lung cancer
therapies. Many combinational therapies of 20S PIs with conventional chemotherapy were shown to
be well tolerated in clinical trials. However, there have not been any consistent data showing the
beneficial effects of such proteasome inhibitor-based therapies. Low clinical efficacy of 20S PIs in
lung cancer patients may be due to low drug penetration, the status of 20S proteasomes, oncogene
expressions and the inherited or acquired resistance. Potential mechanisms of PI resistance or low or
no clinical activity in lung cancer cells might include alteration of apoptotic proteins, overexpression
or alteration of β5 subunit, or upregulation of heat shock proteins. Various cutting-edge strategies to
counter this resistance or improve 20S PIs’ efficacy in lung cancer cells have been reviewed which
include novel combination therapies, new drug delivery systems, development of more potent PIs,
and targeting different sites of the UPS. A better understanding of PI resistance mechanisms in lung
cancer cells can help improve current clinical treatment strategies and clinical outcomes.
