BCL6 drives an oncogenic transcriptional and epigenetic program in NSCLC whose inhibition results in antineoplastic activity in vivo

BCL6 is an oncogenic transcription factor that represses multiple target genes by recruiting three essential co-repressors (SMRT, NCOR, BCOR) via its BTB domain. These, in turn, serve as scaffold to form distinct complexes with various chromatin remodelers. We found that BCL6 is required to sustain oncogenic features in NSCLC such as cell proliferation and colony formation. Furthermore, we demonstrated that BCL6 allows NSCLC cells to survive several stress conditions including exposure to DNA damaging agents. Although these data demonstrated a critical role of BCL6 in NSCLC oncogenesis, the mechanism underlying its oncogenic activity remains unknown. To elucidate the role of BCL6 in NSCLC, we used the small molecule FX1 which specifically disrupts the interaction between the BTB domain and its essential corepressors (Kd 7+/- 3 uM). An in vitro screening demonstrated that FX1 impaired the survival of 6/15 (40%) BCL6-positive NSCLC cell lines that we considered as BCL6-dependent. Furthermore, FX1 (25mg/kg, every other day) significantly decreased the tumor growth of two BCL6-dependent human NSCLC xenograft models (p Citation Format: Rossella Marullo, Maria V. Revuelta, Yong Ai, Fengtian Xue, Leandro Cerchietti. BCL6 drives an oncogenic transcriptional and epigenetic program in NSCLC whose inhibition results in antineoplastic activity in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1288.