Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Kras-driven non-small-cell lung cancers (NSCLCs) represent a significant cause of cancer mortality with few effective treatments.
• Elevated levels of Ezh2 (enhancer of zeste homolog 2), the enzymatic component of polycomb repressive complex 2 (PRC2), are frequently observed in NSCLCs.

Purpose of the Study:

• To investigate the efficacy of Ezh2 inhibitors, such as GSK126, as monotherapy or in combination with chemotherapy for Kras-driven NSCLC.
• To elucidate the adaptive mechanisms, including inflammatory pathways and oncogene activation, that allow NSCLC cells to overcome EZH2 inhibition.

Main Methods:

• Utilized orthotopic Kras-driven NSCLC mouse models with homogeneous Ezh2 expression.
• Conducted in vivo RNAi screening to identify PRC2/NF-κB targets mediating tumor progression.
• Performed in vitro compound screening to link GSK126-induced inflammation and therapeutic vulnerabilities to RNA synthesis and proteostasis.

Main Results:

• NSCLC grafts demonstrated sensitivity to EZH2 inhibition by GSK126, but also activated an inflammatory program involving NF-κB signaling.
• Tumor cells developed resistance to GSK126's antiproliferative effects through adaptive responses.
• GSK126 treatment sensitized NSCLCs to a combination of nimesulide and bortezomib, targeting RNA synthesis and proteostasis.

Conclusions:

• Ezh2 inhibition can restrict NSCLC proliferation but also triggers adaptive responses that may limit therapeutic efficacy.
• Targeting these adaptive inflammatory and proteostasis pathways, potentially with combination therapies like nimesulide and bortezomib, may improve treatment outcomes for Kras-driven NSCLCs.