| 論文作者 |
Yan, YR; Wang, N; Xing, BW; Yang, M; Shang, J; Bao, YF; Xiao, LX; Zhang, NX; Ren, YP; Liu, CN; Chen, YT; Han, H; Pan, YJ; Lv, L; Zong, WX; Ji, HB; Zhan, CY; Wang, ZF; Chen, HQ; Wang, YB |
| 摘要 |
Dysregulated RNA splicing has emerged as a pervasive yet understudied feature of cancer. The small GTPase RAC1 undergoes splicing changes in multiple cancers. However, the in vivo functional disparities between the two major RAC1 isoforms, RAC1B and the canonical RAC1A, and their therapeutic implications in cancer remain largely unexplored. Here, RAC1B is found to be significantly upregulated in lung adenocarcinoma (LUAD) patients, particularly in those harboring EGFR mutations. Through isoform-specific overexpression and depletion assays in murine and cellular models of EGFR-mutant LUAD, it is revealed that RAC1B, but not RAC1A, promotes LUAD cell proliferation and tumor growth. Mechanistically, RAC1B stabilizes EGFR by inhibiting its lysosome trafficking and degradation. This function is mediated by the specific binding of RAC1B to the guanine nucleotide exchange factor GDS1, which activates RAC1B. The splicing factor RBM10 which is frequently mutated in LUAD is further identified as a negative regulator of RAC1B. Importantly, utilizing LUAD patient-derived organoid and xenograft models, it is demonstrated that targeting RAC1B potently suppresses tumor growth and enhances the efficacy of EGFR inhibitors. Together, the findings delineate functional differences and underlying mechanisms of RAC1 isoforms in LUAD tumorigenesis, highlighting a promising therapeutic route via targeting RAC1B for lung cancer. |
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