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journal article·2025-09Open access

Splicing Shift of RAC1 Accelerates Tumorigenesis and Defines a Potent Therapeutic Target in Lung Cancer

Yueren Yan, Ning Wang, Bowen Xing, Min Yang, Jun Shang, Yufang Bao, Lixing Xiao, Ningxia Zhang, Yunpeng Ren, Chunnan Liu, Yuting Chen, Han Han, Yunjian Pan, Lei Lv, Wei‐Xing Zong, Hongbin Ji, Changyou Zhan, Zefeng Wang, Haiquan Chen, Yongbo Wang

Advanced Science· Volume 12· Issue 33
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Source abstract

Abstract

Abstract 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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Research context

OpenAlex topics: RNA Research and Splicing · RNA and protein synthesis mechanisms · RNA modifications and cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering Fudan University Shanghai Cancer Center Shanghai 200032 China

Institute of Thoracic Oncology Fudan University Shanghai 200032 China

Department of Oncology Shanghai Medical College Fudan University Shanghai 200032 China

Department of Cellular and Genetic Medicine School of Basic Medical Sciences & Minhang Hospital Fudan University Shanghai 200032 China

University of Chinese Academy of Sciences CAS Key Laboratory of Computational Biology Shanghai Institute of Nutrition and Health Chinese Academy of Sciences Shanghai 200031 China

Department of Pharmacology School of Basic Medical Sciences & State Key Laboratory of Molecular Engineering of Polymers Fudan University Shanghai 200032 China

School of Life Science Southern University of Science and Technology Shenzhen Guangdong 518055 China

Department of Respiratory and Critical Care Medicine Center for Oncology Medicine The Fourth Affiliated Hospital of School of Medicine International School of Medicine International Institutes of Medicine Zhejiang University Yiwu 322000 China

Zhejiang Key Laboratory of Precision Diagnosis and Treatment for Lung Cancer Yiwu 322000 China

Ministry of Education Key Laboratory of Metabolism and Molecular Medicine Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Fudan University Shanghai 200032 China

Department of Chemical Biology Ernest Mario School of Pharmacy Rutgers‐the State University of New Jersey Piscataway NJ 08854 USA

Key Laboratory of Multi‐Cell Systems Shanghai Institute of Biochemistry and Cell Biology Center for Excellence in Molecular Cell Science Chinese Academy of Sciences Shanghai 200031 China

Shanghai Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention School of Basic Medical Sciences Fudan University Shanghai 200032 China

Funding

National Natural Science Foundation of China · National Key Research and Development Program of China

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