Dihydroartemisinin inhibits mutant KRAS to potentiate regorafenib plus anti-PD-1 in KRAS-mutant colorectal cancer liver metastases.

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, and liver metastases stands as a leading contributor to its high mortality rate in advanced stages. Regorafenib plus anti-PD-1 is a new therapeutic option for patients with colorectal cancer liver metastases (CRCLM). However, a considerable number of patients have not benefited from it. In this study, KRAS mutation was identified associated with resistance to regorafenib plus anti-PD-1 in CRCLM. Dihydroartemisinin (DHA), a clinically approved anti-malaria agent, was verified to selectively downregulate KRASG12D mutant with no discernible influences on wild-type KRAS, which is consistent with the higher sensitivity of KRAS-mutant CRC cells and organoids to DHA treatment. In preclinical KRASG12D CRCLM models, DHA substantially potentiated the therapeutic efficacy of regorafenib plus anti-PD-1 by remodeling the tumor immune microenvironment, including enhancing the cytotoxicity of CD8+ effector T cells and promoting pro-inflammatory macrophage polarization. Mechanically, DHA could restore interferon response that was impaired by oncogenic KRAS mutations, and inhibit ERBB signaling activation induced by regorafenib. Collectively, these findings support DHA as a potential adjunct to regorafenib plus anti-PD-1 for KRASG12D CRCLM and suggest a therapeutic strategy with translational potential for KRAS-driven malignancies. Black arrows: Mutant KRAS can impair IFN response to inhibit CD8+ T cells anti-tumor immune response, thus attenuating the efficacy of PD-1 mAb therapy. Red arrows: DHA can inhibit mutant KRAS expression by promoting autophagy-lysosome pathway. Orange arrows: Regorafenib plays a role of anti-angiogenesis, but also probably induces ERBB signaling activation, which can inhibit IFN response via upregulating p-Erk1/2 and p-Akt, thus causing resistance to regorafenib treatment. Green arrows: The treatment of DHA can drive macrophages polarization to pro-inflammation phenotype (M1-like), probably via the enhancement of TNFα expression. This Figure was produced by Figdraw.