WNT-driven immune evasion promotes malignant transformation of BRAF-mutant colorectal cancer.

Targeting the ANKRD54/ELOVL6 axis suppresses malignancy in BRAF mutant colorectal cancer by disrupting fatty acid metabolism and promoting ferroptosis

BRAF-mutant (BRAF-MT) colorectal cancer (CRC) represents a clinically aggressive subtype characterized by distinct biological features and significantly worse prognosis compared to BRAF wild-type (BRAF-WT) CRC, with median survival reduced by approximately 40%. The therapeutic resistance of BRAF-MT CRC stems primarily from BRAF-driven dysregulation of tumor cell proliferation. However, the molecular mechanisms underlying the aggressive phenotype and potential therapeutic vulnerabilities remain incompletely understood. Bioinformatic analyses were employed to identify candidate genes. A combination of in vitro (cell proliferation, clonal formation), ex vivo (patient-derived and mouse intestinal organoids), and in vivo (xenograft models) assays were used to assess oncogenic function. Mechanistic investigations included Western blotting, qRT-PCR, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and luciferase reporter assays to delineate the regulatory axis. Fatty acid metabolism and ferroptosis were evaluated by a combination of metabolomic, biochemical, and cellular assays. Bioinformatic screening identified ankyrin repeat domain 54 (ANKRD54) as selectively overexpressed in BRAF-MT CRC and significantly associated with adverse prognosis. Inhibition of ANKRD54 markedly suppressed clonogenic potential, cellular proliferation in vitro, organoid formation in both PDOs and cKI mouse-derived organoids, and tumor growth in vivo. Mechanistically, lysine acetyltransferase 2 A (KAT2A) promoted ANKRD54 transcriptional activation through H3K27 acetylation. ANKRD54 subsequently formed a functional complex with CCAAT/enhancer binding protein beta (CEBPB), cooperatively inducing ELOVL fatty acid elongase 6 (ELOVL6) expression. This KAT2A-mediated ANKRD54/CEBPB/ELOVL6 transcriptional axis reprogrammed fatty acid metabolism, selectively suppressing ferroptosis in BRAF-MT CRC. Pharmacological targeting of either ANKRD54 or ELOVL6 substantially enhanced the therapeutic efficacy of Vemurafenib-based treatment in BRAF-MT CRC models. Clinical data corroborated that elevated ANKRD54 expression promoted malignant progression and predicted poor outcomes through this ELOVL6-dependent metabolic pathway. This study elucidates a novel KAT2A-mediated ANKRD54/CEBPB/ELOVL6 axis driving aggressive tumor behavior through regulating fatty acid metabolic and ferroptosis evasion. These findings establish ANKRD54 and ELOVL6 as promising therapeutic targets for combination strategies to overcome therapeutic resistance in BRAF-MT CRC patients.

KRAS mutations as architects of the tumor immune microenvironment: implications for combination therapies

Oncogenic KRAS mutations rank among the most prevalent driver alterations in human malignancies, reaching near-universal frequency (~98%) in pancreatic ductal adenocarcinoma (PDAC) and high prevalence in colorectal cancer (CRC, ~52%) and lung adenocarcinoma (LAC, ~32%). Beyond their canonical roles in promoting cell-intrinsic proliferation and survival through the MAPK/ERK and PI3K/AKT cascades, KRAS mutations actively sculpt a profoundly immunosuppressive tumor microenvironment (TME), which constitutes a major barrier to both targeted therapy and immunotherapy. Through coordinated programs encompassing inflammatory cytokine secretion, downregulation of antigen presentation machinery, tumor-associated macrophage (TAM) reprogramming, myeloid-derived suppressor cell (MDSC) expansion, and PD-L1 upregulation, KRAS-mutant tumors establish robust immune exclusion. These programs are further stratified by co-mutations in STK11 , KEAP1 , and TP53 , which define distinct immune phenotypes ranging from inflamed to profoundly immune-excluded “cold” tumors. The recent approval of covalent KRAS G12C inhibitors, sotorasib and adagrasib, has revealed that targeted KRAS blockade can remodel the TME toward an immunostimulatory state, providing a mechanistic rationale for combining KRAS-directed agents with immune checkpoint blockade, STING agonists, and neoantigen vaccines. This mini-review synthesizes the current knowledge of KRAS-immune crosstalk, highlights existing controversies and research gaps, and evaluates emerging combination strategies designed to convert immune exclusion into durable anti-tumor immunity.

Furin sustains tumor-promoting signals in KRAS- and BRAF-mutated colorectal cancer by engaging the TGF-β1-COX-2 axis in a reciprocal regulatory network

Treatment Responses Alter Myeloid Activation in BRAF-Mutant Melanoma 2252856

Melanoma is responsible for 80% of skin cancer-related deaths. Approximately 50% of melanoma patients carry the BRAFV600E mutation, which promotes tumor growth. While the use of BRAF inhibitors (BRAFi) has improved outcomes, acquired resistance is a persistent clinical challenge and the impact of BRAFi resistance on the immune tumor microenvironment (iTME) is incompletely understood. We have shown that the addition of the synthetic triterpenoid CDDO-Me to the BRAFi PLX4720 arrested resistance and significantly reduced tumor burden, while CDDO-Me as a single agent or in combination with BRAFi prior to resistance was ineffective. Thus, we hypothesize that this disparity in treatment efficacy may be attributable to temporally regulated BRAFi treatment-induced changes to the iTME. Drug-induced changes in the iTME pre and post-resistance were characterized in tumors of engrafted transgenic BRAF/Pten mice using scRNA-seq, flow cytometry, and ELISA. T cell proliferation assays were used to assess functional changes in tumor-conditioned myeloid cells. BRAFi treatment attenuated immunosuppressive myeloid activation pre-resistance, while BRAFi resistance was associated with enhanced tumor-associated macrophage (TAM) recruitment and immunosuppressive myeloid subset activation. However, the addition of CDDO-Me to BRAFi at resistance reversed these outcomes and rescued the ability of TAMs to induce T cell proliferation. The iTME changes with tumor progression and responds dynamically to BRAFi treatment and resistance. This work establishes for the first time that BRAFi promotes myeloid-mediated induction of T cell activation, which is lost at resistance but can be rescued with the addition of CDDO-Me. Because BRAFi resistance and iTME immunosuppression is reversed by CDDO-Me treatment, these results provide the foundation for its potential use in combination therapies for melanoma. Dartmouth Health Cancer Center Developmental Funding (Prouty Pilot Grant) Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Recurrent PIK3CA-E545K mutation promotes cervical cancer growth and invasion via AKT/mTOR signaling

KRAS Mutations Reprogram RNA m6A Modifications to Drive CD73-Dependent Immune Evasion in Colorectal Cancer.

KRAS mutations, present in about 40% of colorectal cancers (CRCs), are strongly associated with an immunosuppressive tumor microenvironment characterized by restricted immune infiltration and poor responses to immunotherapy. Here, we found that KRAS mutations remodel the N6-methyladenosine (m6A) epitranscriptome to promote immune evasion. Methylated RNA immunoprecipitation sequencing revealed that KRAS-mutant cells exhibit increased m6A deposition on CD73 mRNA, enhancing its stability through IGF2BP3. TEAD4-dependent recruitment of the METTL3 methyltransferase complex induced the m6A modification, identifying TEAD4 as a spatial regulator of m6A deposition. Functionally, METTL3 knockdown in KRAS-mutant syngeneic tumors suppressed tumor growth and restored antitumor immunity by increasing CD8⁺ T-cell and NK-cell infiltration in a CD73-dependent manner. Moreover, METTL3 inhibition synergized with anti-PD-1 therapy and a CD73 inhibitor to reduce tumor burden. Together, these findings demonstrate that KRAS-driven m6A remodeling is a key mechanism of immune suppression in CRC and highlight METTL3 as a promising therapeutic target.