BCL6 is regulated by the MAPK/ELK1 axis and promotes KRAS-driven lung cancer

Mutational activation of KRAS is a common oncogenic event in lung cancer, yet effective therapies are still lacking. Here, we identify B cell lymphoma 6 (BCL6) as a lynchpin in KRAS-driven lung cancer. BCL6 expression was increased upon KRAS activation in lung tumor tissue in mice and was positively...

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Published in:The Journal of clinical investigation 2022-11, Vol.132 (22), p.1-15
Main Authors: Li, Kun, Liu, Yanan, Ding, Yi, Zhang, Zhengwei, Feng, Juanjuan, Hu, Jiaxin, Chen, Jiwei, Lian, Zhengke, Chen, Yiliang, Hu, Kewen, Chen, Zhi, Cai, Zhenyu, Liu, Mingyao, Pang, Xiufeng
Format: Article
Language:English
Subjects:
Bcl-6 protein
Biomedical research
Cell cycle
DNA biosynthesis
DNA damage
Genes
K-Ras protein
Kinases
Lung cancer
Lymphoma
MAP kinase
Mortality
Mutants
Mutation
Oncology
Protein expression
Proteins
Signal transduction
Therapeutic targets
Therapeutics
Tumor cell lines
Tumorigenesis
Tumors
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Summary:Mutational activation of KRAS is a common oncogenic event in lung cancer, yet effective therapies are still lacking. Here, we identify B cell lymphoma 6 (BCL6) as a lynchpin in KRAS-driven lung cancer. BCL6 expression was increased upon KRAS activation in lung tumor tissue in mice and was positively correlated with the expression of KRAS-GTP, the active form of KRAS, in various human cancer cell lines. Moreover, BCL6 was highly expressed in human KRAS-mutant lung adenocarcinomas and was associated with poor patient survival. Mechanistically, the MAPK/ERK/ELK1 signaling axis downstream of mutant KRAS directly regulated BCL6 expression. BCL6 maintained the global expression of prereplication complex components; therefore, BCL6 inhibition induced stalling of the replication fork, leading to DNA damage and growth arrest in KRAS-mutant lung cancer cells. Importantly, BCL6-specific knockout in lungs significantly reduced the tumor burden and mortality in the LSL-KrasG12D/+ lung cancer mouse model. Likewise, pharmacological inhibition of BCL6 significantly impeded the growth of KRAS-mutant lung cancer cells both in vitro and in vivo. In summary, our findings reveal a crucial role of BCL6 in promoting KRAS-addicted lung cancer and suggest BCL6 as a therapeutic target for the treatment of this intractable disease.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI161308