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    Home > Biochemistry News > Biotechnology News > Saiye animal models helped Sun Yat-sen University and other teams discover potential therapeutic targets for KRAS mutated cancers

    Saiye animal models helped Sun Yat-sen University and other teams discover potential therapeutic targets for KRAS mutated cancers

    • Last Update: 2022-11-15
    • Source: Internet
    • Author: User
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    in the RAS oncogene have been found in about 30% of human cancers.
    Among them, the mutation frequency of KRAS is much higher than that of HRAS and NRAS
    For example, about 12-15% of patients with non-small cell lung cancer carry the KRAS G12C mutation, and more than 90% of patients with KRAS ductal adenocarcinoma (PDAC), especially the KRAS G12D and KRASG12V subtypes.

    However, the development of RAS inhibitors has been so difficult that RAS is considered an "undruggable target.
    Recently, small molecule compounds that directly target the KRASG12C mutation have been approved for therapeutics, but targeting other KRAS mutations
    is still considered clinically impractical.

    Recently, researchers from the First Affiliated Hospital of Sun Yat-sen University and Nanjing University have found that a protein RASON encoded by a long chain of non-coding RNA between genes (LINC00673) is a key regulator of the oncogenic RAS signaling pathway and is expected to become a therapeutic target for KRAS mutated
    The results were published Oct.
    14 in
    the journal Cell Research.

    Research materials and methods

    In this study, the researchers used multiple pancreatic cancer cell lines and knocked out the rason gene
    from multiple cell lines using CRISPR technology.
    To study pancreatic tumor generation, they also used multiple mouse models and commissioned Saiye Biologics to construct Rason-/− mice
    They determined RASON expression by western blotting and LC-MS analysis, and analyzed RASON-KRAS interactions
    by experiments such as immunoprecipitation, surface plasmon resonance, and nuclear magnetic resonance.

    Research results

    (1) RASON protein is associated with poor prognosis of PDAC

    There are a large number of non-coding regions in the human genome that were previously thought to be non-coding proteins, but in recent years translationome studies have identified hundreds of functional peptides or proteins
    from the non-coding regions.
    The researchers set out to analyze
    the noncoding regions of pancreatic cancer samples.

    After comparing the three PDAC cell lines with normal pancreatic duct cell lines, they found differential translations of long non-coding RNA (lincRNAs) between 8 genes, with LINC00673 ranking first
    Comparison of tumor samples from PDAC patients with normal tissues adjacent to cancer also showed that LINC00673 was differentially expressed
    They confirmed by western blot analysis that LINC00673 encodes a 108-amino acid protein and named it RASON

    In a separate cohort of 105 PDAC cancer samples and paired normal pancreas samples, the researchers found that LINC00673 was highly expressed in cancer samples and that its expression was positively correlated
    with tumor grade.
    In line with this, the expression of the rason protein in cancer tissues was also significantly increased and positively correlated with shorter tumor grade and overall survival (Figure 1).

    These results suggest that RASON is an oncoprotein that acts as a prognostic marker for

    Figure 1.
    RASON is overexpressed in human pancreatic cancer

    (2) RASON is essential for KRAS-driven tumorigenesis

    To investigate RASON's potential function in PDAC, the researchers constructed two pancreatic cancer cell lines
    that knocked out RASON.
    They found that the RAS downstream signaling pathway was inhibited after rason knockout, and the downstream pathway
    was enhanced after rason overexpression.
    In addition, they generated Rason-/− homologate knockout (Rason−/−) mice (which were provided by Saiye).

    Both embryonic fibroblasts and pancreatic tissues of Rason−/− mice showed significant downregulation of RAS signaling pathway, indicating that rason was involved in the regulation
    of oncogenic KRAS signaling pathway.

    To explore whether RASON is involved in KRAS-driven tumorigenesis, they used RAS-less MEF cell lines stably transfected with KRAS G12D or KRASG12V and tested the effect of
    Rason KO on KRAS-induced MEF cell transformation.
    They generated two Rason KO clones and found that Rason KO almost completely reduced the tumorigenic potential
    of KRAS G12D or KRASG12V MEF cells.
    Subcutaneous tumorigenesis experiments in nude mice also confirmed the key role
    of rason in mutation-induced MEF cell transformation.
    Compared to control cells, Rason KO almost completely eliminates tumor formation

    The researchers then crossed Rason-/− mice with KC mice, a mature model for studying the early stages of PDAC, to generate KCR mice
    KCR mice had a significant reduction in all precancerous lesion formation at 6 and 9 months of age compared to KC mice, suggesting that RASON was involved in the early stages of KRAS-driven pancreatic tumor formation (Figure 2).

    Studies on another classic PDAC model mouse (KPC mouse) confirmed this
    These data suggest that RASON is required for
    KRAS-driven pancreatic tumorigenesis in mice.

    Figure 2.
    RASON is required for KRAS-driven pancreatic tumorigenesis

    Immunoprecipitation analysis showed a direct interaction
    between RASON and KRAS.
    Surface plasmon resonance analysis (SPR) showed that RASON binds
    to KRAS G12D and KRASG12V with very high affinity.
    The results of nuclear magnetic resonance (NMR) titration experiments also strongly support the direct binding of
    rason to KRAS.
    Subsequent analyses showed that rason inhibits GTPase-activated protein (GAP)-induced GTP hydrolysis, keeping KRAS in an activated state at all times (Figure 3).

    Figure 3.
    Schematic diagram of RASON's regulation of oncogenic RAS signaling pathways

    (3) RASON is a potential therapeutic target for PDAC

    Due to the presence of KRAS mutations, most patients with PDAC develop resistance
    to EGFR inhibitors (cetuximab).
    However, the combination of cetuximab and RASON shRNA minimized tumor growth in nude mice, suggesting that rason inhibition made KRAS-mutated cancer cells sensitive
    to cetuximab.
    The effect of this combination therapy has also been demonstrated on organoids derived from PDAC patients, indicating that RASON is a potential therapeutic target for PDAC patients with KRAS mutations


    Overall, the researchers identified a rason protein
    that is essential for KRAS signaling.
    This protein encoded by lincRNA binds directly to KRAS, allowing KRAS to stabilize in an over-activated state bound to GTP and is therefore necessary for
    KRAS-driven tumorigenesis and tumor maintenance.
    A decrease in RASON increases pancreatic cancer's sensitivity
    to EGFR inhibitors.
    They believe that for the "undruggable" KRAS signaling pathway in human cancer, the KRAS−rason interaction may be an attackable target

    Original text search

    Cheng, R.
    , Li, F.
    , Zhang, M.
    et al.
    A novel protein RASON encoded by a lncRNA controls oncogenic RAS signaling in KRAS mutant cancers.
    Cell Res (2022).

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