Proteasome inhibitors block DNA repair and radiosensitize non-small cell lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Radiotherapy

Background:

• Locally advanced non-small cell lung cancer (NSCLC) often shows resistance to standard treatments like radiation therapy (RT), chemotherapy, and surgery.
• Identifying novel therapeutic targets is crucial for improving treatment outcomes in NSCLC patients.

Purpose of the Study:

• To identify gene targets that enhance the efficacy of radiation therapy in non-small cell lung cancer (NSCLC).
• To investigate the role of proteasome subunits in NSCLC radioresistance and explore proteasome inhibition as a radiosensitization strategy.

Main Methods:

• Whole genome RNA interference (RNAi) screens were conducted to identify gene knockdowns increasing NSCLC cytotoxicity.
• The effects of proteasome inhibition on DNA repair pathways, including homologous recombination (HR), were assessed.
• Synergistic effects of radiation and proteasome inhibition were evaluated in vitro and in vivo using NSCLC cell lines and xenograft mouse models.

Main Results:

• Proteasome subunits, particularly PSMA1, were identified as top hits in RNAi screens for enhancing NSCLC cytotoxicity.
• Proteasome inhibition significantly decreased homologous recombination (HR) by 80-90% and reduced the expression of HR genes BRCA1 and FANCD2.
• Combined treatment of radiation with proteasome inhibition demonstrated synergistic effects, markedly increasing survival in a mouse model of NSCLC.

Conclusions:

• Proteasome inhibition, specifically targeting PSMA1, is a promising strategy for radiosensitizing non-small cell lung cancer (NSCLC).
• This radiosensitization occurs through the inhibition of NF-κB-mediated expression of Fanconi Anemia/HR DNA repair genes, thereby enhancing tumor control.