TY - JOUR AU - Li, Kun AU - Liu, Yanan AU - Ding, Yi AU - Zhang, Zhengwei AU - Feng, Juanjuan AU - Hu, Jiaxin AU - Chen, Jiwei AU - Lian, Zhengke AU - Chen, Yiliang AU - Hu, Kewen AU - Chen, Zhi AU - Cai, Zhenyu AU - Liu, Mingyao AU - Pang, Xiufeng T1 - BCL6 is regulated by the MAPK/ELK1 axis and promotes KRAS-driven lung cancer PY - 2022/11/15/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI161308 VL - 132 IS - 22 UR - https://doi.org/10.1172/JCI161308 PB - The American Society for Clinical Investigation ER -