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Ref Type Journal Article
PMID (37504287)
Authors Hong S, Jeon M, Kwon J, Park H, Lee G, Kim K, Ahn S
Title Targeting RAF Isoforms and Tumor Microenvironments in RAS or BRAF Mutant Colorectal Cancers with SJ-C1044 for Anti-Tumor Activity.
Journal Vol Issue Date Pages Journal Short Title
Current issues in molecular biology 45 7 2023 Jul 13 5865-5878 Curr Issues Mol Biol
URL
Abstract Text Colorectal cancer (CRC) is a significant global health issue characterized by a high prevalence of KRAS gene mutations. The RAS/MAPK pathway, involving KRAS, plays a crucial role in CRC progression. Although some RAS inhibitors have been approved, their efficacy in CRC is limited. To overcome these limitations, pan-RAF inhibitors targeting A-Raf, B-Raf, and C-Raf have emerged as promising therapeutic strategies. However, resistance to RAF inhibition and the presence of an immunosuppressive tumor microenvironment (TME) pose additional obstacles to effective therapy. Here, we evaluated the potential of a novel pan-RAF inhibitor, SJ-C1044, for targeting mutant KRAS-mediated signaling and inhibiting CRC cell proliferation. Notably, SJ-C1044 also exhibited inhibitory effects on immunokinases, specifically, CSF1R, VEGFR2, and TIE2, which play crucial roles in immune suppression. SJ-C1044 demonstrated potent antitumor activity in xenograft models of CRC harboring KRAS or BRAF mutations. Importantly, treatment with SJ-C1044 resulted in increased infiltration of T cells and reduced presence of tumor-associated macrophages and regulatory T cells within the TME. Thus, SJ-C1044 shows immunomodulatory potential and the ability to enhance antitumor responses. The study underscores the therapeutic potential of SJ-C1044 as a novel pan-RAF inhibitor capable of targeting oncogenic signaling pathways and overcoming immune suppression in CRC.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SJ-C1044 SJ-C1044 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
SJ-C1044 SJ C1044|SJC1044 RAF Inhibitor (Pan) 28 SJ-C1044 is a pan-RAF inhibitor, which potentially decreases immune suppression and tumor growth (PMID: 37504287).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E colorectal cancer sensitive SJ-C1044 Preclinical - Cell line xenograft Actionable In a preclinical study, SJ-C1044 decreased growth in a colorectal cancer cell line harboring BRAF V600E in culture and inhibited tumor growth in a cell line xenograft model (PMID: 37504287). 37504287