Abstract Background 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. Citation Format: Toshiaki Takahashi, Kunitoshi Shigeyasu, Kazuya Moriwake, Masashi Kayano, Hibiki Umeda, Kazuhiro Yoshida, Sho Takeda, Yuki Matsumi, Hiroyuki Kishimoto, Tomokazu Fuji, Kazuya Yasui, Hideki Yamamoto, Kosei Takagi, Hiroyuki Michiue, Yoshiko Mori, Fuminori Teraishi, Hiroshi Tazawa, Yuzo Umeda, Ajay Goel, Toshiyoshi Fujiwara. Secreted BRAF V600E drives ADAR1-dependent RNA editing and defines a therapeutic vulnerability in colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3193.
Takahashi et al. (Fri,) studied this question.