Combination of RAS(ON) G12C-selective inhibitors with SHP2 inhibitors to sensitize tumours to immune checkpoint blockade

Lung cancer driven by KRAS mutations, particularly the G12C variant, remains a significant challenge in non-small cell lung cancer (NSCLC) treatment. KRAS mutations promote tumor growth and survival, making them ideal therapeutic targets. Although KRASG12C inhibitors such as adagrasib and sotorasib, which target the inactive, GDP-bound form of KRAS, have shown initial success, their efficacy is limited by the rapid development of resistance in many patients.

To address this issue, the authors of this study explored combining RMC-4998, a selective inhibitor targeting the active, GTP-bound form of KRASG12C, with RMC-4550, an SHP2 inhibitor. SHP2 mediates signaling from receptor tyrosine kinases (RTKs), contributing to the reactivation of the RAS pathway even when KRASG12C inhibitors are applied. This dual approach aims to suppress KRAS signaling at multiple levels and remodel the tumor microenvironment (TME) to enhance immune responses.

In cell studies, RMC-4998 significantly outperformed traditional KRAS inhibitors by rapidly reducing KRASG12C-mutant NSCLC cell viability and inhibiting MAPK signaling. However, ERK phosphorylation, a marker of pathway reactivation, rebounded after 24-48 hours, indicating adaptive resistance. When RMC-4550 was added, the rebound effect was suppressed, leading to sustained MAPK inhibition, more significant reductions in cell viability, and increased apoptosis. These effects were observed over long-term treatment, demonstrating that this combination prevents the development of adaptive resistance.

In mouse models of KRASG12C-mutant lung cancer, the combination therapy showed remarkable efficacy. In immunocompetent mice with immunogenic tumors, the dual treatment led to complete tumor regressions in 75% of cases treated with RMC-4998 and in 14.3% with RMC-4550 alone. Significantly, the combination therapy prevented tumor relapse in 100% of treated mice, resulting in durable tumor eradication. Moreover, the combination induced immune memory, as mice remained tumor-free after being rechallenged with cancer cells, showing that the treatment had stimulated lasting anti-tumor immunity.

In more aggressive, immune-excluded tumor models, which typically resist immune checkpoint blockade (ICB) therapies, the combination therapy sensitized tumors to anti-PD-1 treatment. When combined with anti-PD-1 therapy, the treatment resulted in 37.5% complete tumor regressions in these resistant tumors, compared to marginal responses with ICB alone or either RMC-4998 or RMC-4550 monotherapy. The combination of RMC-4998 and RMC-4550 not only slowed tumor growth but also reprogrammed the TME, increasing CD8+ T cell infiltration and suppressing immunosuppressive myeloid cells.

In an orthotopic model of lung cancer, where tumors are located in their natural tissue environment, RMC-4998 treatment resulted in significant tumor shrinkage, with over half of the tumors regressing completely. However, relapse occurred in about 50% of these cases after treatment cessation. When RMC-4550 was added, relapse rates dropped to just 10%, highlighting the benefit of combining both inhibitors in preventing early tumor recurrence.

These preclinical results suggest that combining KRAS(ON) G12C-selective inhibitors with SHP2 inhibition has the potential to dramatically enhance treatment outcomes in KRAS-mutant lung cancers, especially those resistant to standard therapies. The combination not only targets cancer cell survival but also promotes immune responses, offering a promising strategy for achieving durable tumor regressions and improved patient survival. 

References

Anastasiou, P., Moore, C., Rana, S. et al. Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade. Nat Commun 15, 8146 (2024). https://doi.org/10.1038/s41467-024-52324-3