BCL6 is regulated by the RAS/MAPK/ELK axis and promotes KRAS-driven lung cancers

Mutational activation of KRAS represents a common oncogenic event in lung cancers and still lacks effective treatments so far. Here, we identify the proto-oncogene B-cell lymphoma 6 (BCL6) as a lynchpin for KRAS dependence. BCL6 transcription was markedly promoted upon inducible activation of KRAS in either LSL-KrasG12D mice lung tumor tissue or engineered KRAS isogenic cell lines. Constitutive expression of BCL6 was also observed in patients with KRAS-mutant lung adenocarcinoma and associated with poor survival. Employing chemical and genetic screens, we characterized that the MAPK/ELK1 axis downstream of KRAS directly regulated BCL6 expression. Genetic depletion or pharmacological inhibitor targeting BCL6 preferentially impedes the proliferation of KRAS-mutant lung cancer cells by suppressing pre-RC protein expression in cycling cells, ultimately leading to stalled replication and DNA damage in vitro. Accordingly, targeted inhibition of BCL6 significantly reduced tumor burden and mortality in LSL-KrasG12D/+ and patient-derived lung cancer xenograft mouse models in vivo. Taken together, these findings reveal an oncogenic role of BCL6 in promoting KRAS-addicted lung cancers and define that BCL6 inhibition confers a targetable vulnerability for this kind of disease. 7 samples are uploaded. RNA-seq was performed for HPNE cells,HPNE/KRAS G12V cells (HK) and HK/siBCL6 cells (HK cells treated with siBCL6); MEF1 cells and MEF1/KRAS G12D cells, MEF2/KRAS G12D cells and MEF2/ KRAS G12D/siBCL6 cells (MEF2/ KRAS G12D cells treated with siBCL6); each sample has three biological replicates.