Pulsatile MEK Inhibition Improves Anti-tumor Immunity and T Cell Function in Murine Kras Mutant Lung Cancer

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• KRAS is a key driver oncogene in non-small-cell lung cancer (NSCLC).
• Current MEK inhibitors (MEKis) targeting KRAS pathways often face challenges with drug resistance.
• Optimizing MEKi treatment schedules is crucial for improving therapeutic efficacy.

Purpose of the Study:

• To investigate the impact of pulsatile versus continuous MEKi dosing on T-cell activation and anti-tumor immunity.
• To evaluate the efficacy of pulsatile MEKi treatment in combination with CTLA-4 blockade for KRAS-mutant NSCLC.
• To explore the potential of pulsatile MEKi therapy in overcoming drug resistance and promoting long-term anti-tumor responses.

Main Methods:

• Administered two MEKis (selumetinib and trametinib) using pulsatile and continuous dosing schedules in vivo.
• Assessed T-cell activation, proliferation, and expression of immune checkpoint molecules (CTLA-4, PD-1).
• Evaluated anti-tumor effects, tumor growth delay, and emergence of drug resistance in mouse models.
• Investigated the combination of pulsatile MEKi treatment with CTLA-4 blockade.

Main Results:

• Pulsatile MEKi treatment maintained T-cell activation and proliferation, unlike continuous dosing.
• Cyclical pulsatile MEKi administration increased CTLA-4 and PD-1 expression on T-cells.
• Pulsatile MEKi therapy demonstrated superior anti-tumor effects and delayed drug resistance.
• Combination therapy with pulsatile MEKi and CTLA-4 blockade significantly prolonged survival in mice with KRAS-mutant tumors.

Conclusions:

• Pulsatile MEKi dosing is a promising strategy to enhance T-cell mediated anti-tumor immunity in NSCLC.
• This approach can overcome resistance mechanisms associated with continuous MEKi treatment.
• Combining pulsatile targeted therapy with immunotherapy offers a potent strategy for durable anti-tumor responses and improved survival.