分泌型 BRAF V600E 驱动 ADAR1 依赖性 RNA 编辑并界定结直肠癌的一个治疗弱点

Background & Aims:The BRAF V600E mutation occurs in approximately 8-12% of colorectal cancers (CRC) and confers poor prognosis and therapeutic resistance. Despite the clinical success of combined BRAF and EGFR inhibition in the BEACON trial, resistance rapidly develops. Adenosine-to-inosine RNA editing, which is a post-transcriptional modification driven by adenosine deaminase acting on RNA (ADAR), promotes tumor malignancy and the acquisition of metastatic potential. We previously reported that ADAR1-high macrophages act as mediators of drug resistance and proposed ADAR1-targeted therapy as a potential new approach (Molecular Cancer, 2025). However, the specific patient population likely to benefit from ADAR1-targeted therapy remains unclear. This study investigated whether secreted BRAF V600E protein induces ADAR1-dependent RNA editing to promote tumor progression and therapeutic resistance, and whether JAK inhibition can enhance the efficacy of BRAF/EGFR-targeted therapy. Methods:We combined analysis of clinical CRC tissues, spatial transcriptomics, and RNA sequencing with functional in vitro and in vivo models to characterize BRAF V600E secretion, intracellular distribution, and downstream molecular effects. Pharmacologic inhibition using JAK, EGFR, and BRAF inhibitors was used to evaluate their effects on the ADAR1-RNA editing pathway and associated tumor phenotypes. Results:BRAF V600E-mutant CRC cells secreted the mutant BRAF protein through extracellular vesicles and soluble forms that were detectable in systemic circulation and distant tissues. ADAR1 expression was significantly higher in BRAF-mutant vs. BRAF-wild CRC (p<0.001). Stromal macrophages and fibroblasts internalizing extracellular BRAF V600E exhibited robust ADAR1 induction and hyper-RNA editing via type I interferon-JAK/STAT signaling, promoting immunosuppressive and tumor-supportive phenotypes. Wild-type tumor cells exposed to BRAF V600E protein upregulated ADAR1 and displayed enhanced proliferation and invasion, suggesting horizontal transfer of malignant traits. While combined BRAF/EGFR inhibition in HT29 and Colo205 cells suppressed direct oncogenic signaling, it paradoxically activated the JAK/STAT-ADAR1 axis, increasing RNA editing and resistance. Co-treatment with JAK inhibitors mitigated this effect, restored sensitivity, and suppressed tumor growth in preclinical models. Conclusions:Our findings define a novel circulating ‘BRAF-ADAR1-RNA editing' axis that contributes to immune evasion and resistance in BRAF-mutant CRC. Dual targeting of this pathway, through JAK or ADAR1 inhibition in combination with BRAF/EGFR blockade, represents a rational therapeutic strategy to overcome refractory, mutation-driven colorectal cancer.