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Response and resistance to NF-κB inhibitors in mouse models of lung adenocarcinoma
Wen Xue1, Etienne Meylan, Trudy G Oliver
1Koch Institute for Integrative Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Unlabelled:
Lung adenocarcinoma is a leading cause of cancer death worldwide. We recently showed that genetic inhibition of the NF-κB pathway affects both the initiation and the maintenance of lung cancer, identifying this pathway as a promising therapeutic target. In this investigation, we tested the efficacy of small-molecule NF-κB inhibitors in mouse models of lung cancer. In murine lung adenocarcinoma cell lines with high NF-κB activity, the proteasome inhibitor bortezomib efficiently reduced nuclear p65, repressed NF-κB target genes, and rapidly induced apoptosis. Bortezomib also induced lung tumor regression and prolonged survival in tumor-bearing Kras(LSL-G12D/wt);p53(flox/flox) mice but not in Kras(LSL-G12D/wt) mice. After repeated treatment, initially sensitive lung tumors became resistant to bortezomib. A second NF-κB inhibitor, Bay-117082, showed similar therapeutic efficacy and acquired resistance in mice. Our results using preclinical mouse models support the NF-κB pathway as a potential therapeutic target for a defined subset of lung adenocarcinoma.
Significance:
Using small-molecule compounds that inhibit NF-κB activity, we provide evidence that NF-κB inhibition has therapeutic efficacy in the treatment of lung cancer. Our results also illustrate the value of mouse models in validating new drug targets in vivo and indicate that acquired chemoresistance may later influence bortezomib treatment in lung cancer.
Insights
Small-molecule inhibitors targeting the NF-κB pathway show therapeutic potential for lung adenocarcinoma. Mouse models demonstrate efficacy but also highlight the development of acquired resistance to these treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lung adenocarcinoma is a major global cause of cancer mortality.
- The NF-κB pathway is implicated in both the initiation and progression of lung cancer.
- Identifying effective therapeutic targets for lung adenocarcinoma is critical.
Purpose of the Study:
- To evaluate the efficacy of small-molecule NF-κB inhibitors in preclinical mouse models of lung cancer.
- To investigate the potential of the NF-κB pathway as a therapeutic target for lung adenocarcinoma.
- To assess the development of resistance to NF-κB inhibitors.
Main Methods:
- Utilized murine lung adenocarcinoma cell lines with high NF-κB activity.
- Administered proteasome inhibitor bortezomib and NF-κB inhibitor Bay-117082 to mouse models.
- Assessed reduction in nuclear p65, repression of NF-κB target genes, induction of apoptosis, tumor regression, and survival rates.
- Investigated acquired resistance following repeated treatment.
Main Results:
- Bortezomib effectively reduced nuclear p65, repressed NF-κB target genes, and induced apoptosis in cell lines with high NF-κB activity.
- Bortezomib treatment led to lung tumor regression and prolonged survival in specific Kras(LSL-G12D/wt);p53(flox/flox) mouse models.
- Acquired resistance to bortezomib developed after repeated administration, a phenomenon also observed with Bay-117082.
- Therapeutic efficacy was observed in a subset of lung adenocarcinoma models.
Conclusions:
- NF-κB inhibition demonstrates therapeutic efficacy in lung cancer treatment, supporting its role as a potential drug target.
- Preclinical mouse models are valuable for validating in vivo drug targets and understanding treatment responses.
- Acquired chemoresistance is a significant factor that may impact future bortezomib treatment strategies for lung cancer.
