Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Approved KRAS G12C inhibitors target the inactive form but face rapid resistance in lung cancer.
• RAS pathway reactivation contributes to treatment failure and immune evasion.

Purpose of the Study:

• To evaluate the efficacy of targeting the active, GTP-bound KRAS G12C form using RMC-4998 in preclinical lung cancer models.
• To investigate the combination of RMC-4998 with a SHP2 inhibitor to overcome resistance and enhance anti-tumor immunity.

Main Methods:

• Utilized various immune-competent mouse models of KRAS mutant lung cancer.
• Administered RMC-4998 (RAS G12C inhibitor) alone and in combination with a SHP2 inhibitor.
• Assessed tumor signaling, microenvironment modulation, and immune responses.

Main Results:

• Combined RAS and SHP2 inhibition delayed RAS pathway reactivation and suppressed tumor relapse.
• The combination therapy induced durable responses, immune memory, and immune rejection in different models.
• Combined RAS and SHP2 inhibition sensitized tumors to immune checkpoint blockade.

Conclusions:

• Targeting active RAS G12C with RMC-4998 combined with SHP2 inhibition offers a promising strategy against KRAS mutant lung cancer.
• This combination approach can overcome resistance, remodel the immunosuppressive tumor microenvironment, and enhance efficacy of immune checkpoint inhibitors.