Targeting RAF Isoforms and Tumor Microenvironments in RAS or BRAF Mutant Colorectal Cancers with SJ-C1044 for Anti-Tumor Activity

Colorectal cancer (CRC) is a significant global health issue characterized by high prevalence of KRAS gene mutations. The RAS/MAPK pathway, involving KRAS, plays crucial role in CRC progression. Although some RAS inhibitors have been approved, their efficacy limited. To overcome these limitations, pan-RAF targeting A-Raf, B-Raf, and C-Raf emerged as promising therapeutic strategies. However, resistance to RAF inhibition the presence an immunosuppressive tumor microenvironment (TME) pose additional obstacles effective therapy. Here, we evaluated potential novel inhibitor, SJ-C1044, for mutant KRAS-mediated signaling inhibiting cell proliferation. Notably, SJ-C1044 also exhibited inhibitory effects on immunokinases, specifically, CSF1R, VEGFR2, TIE2, which play roles immune suppression. demonstrated potent antitumor activity xenograft models harboring or BRAF Importantly, treatment with resulted increased infiltration T cells reduced tumor-associated macrophages regulatory within TME. Thus, shows immunomodulatory ability enhance responses. study underscores inhibitor capable oncogenic pathways overcoming suppression CRC.