The Journal of Clinical Investigation (Nov 2022)

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

  • Kun Li,
  • Yanan Liu,
  • Yi Ding,
  • Zhengwei Zhang,
  • Juanjuan Feng,
  • Jiaxin Hu,
  • Jiwei Chen,
  • Zhengke Lian,
  • Yiliang Chen,
  • Kewen Hu,
  • Zhi Chen,
  • Zhenyu Cai,
  • Mingyao Liu,
  • Xiufeng Pang

Journal volume & issue
Vol. 132, no. 22

Abstract

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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.

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