Glutamine antagonists may KEAP lung cancer in check

Area of Science:

• Oncology
• Immunology
• Biochemistry

Background:

• KEAP1/NRF2 mutations are common in lung cancer, leading to impaired antioxidant responses and promoting tumor growth.
• Checkpoint inhibitors have shown efficacy in some lung cancers but resistance remains a challenge.
• Targeting metabolic pathways offers a novel strategy to overcome resistance and enhance antitumor immunity.

Purpose of the Study:

• To investigate the efficacy of the glutamine antagonist DRP-104 in combination with checkpoint inhibitors.
• To determine the impact of DRP-104 on purine synthesis and antitumor immunity in KEAP1/NRF2-mutant lung cancer models.

Main Methods:

• Utilized KEAP1/NRF2-mutant lung cancer cell lines and patient-derived xenografts.
• Administered DRP-104 as a glutamine antagonist to block purine synthesis.
• Combined DRP-104 treatment with checkpoint inhibitors (e.g., anti-PD-1).
• Assessed tumor growth, immune cell infiltration, and cytokine profiles.

Main Results:

• DRP-104 effectively blocked purine synthesis in cancer cells.
• The combination of DRP-104 and checkpoint inhibitors significantly suppressed tumor growth compared to monotherapy.
• Enhanced infiltration and activation of cytotoxic T lymphocytes were observed in tumors treated with the combination therapy.
• DRP-104 treatment modulated the tumor microenvironment, making it more conducive to immune attack.

Conclusions:

• DRP-104, by inhibiting purine synthesis, synergizes with checkpoint inhibitors to promote robust antitumor immunity.
• This combination strategy holds promise for treating patients with KEAP1/NRF2-mutant lung cancers.
• Targeting glutamine metabolism represents a viable approach to overcome resistance to immunotherapy in lung cancer.