In study, we analysed the anti-cancer activity of CBL0137 in Myc-high triple-negative breast cancer models. RNA-Seq was performed on murine syngeneic 4T1.2 tumours following one week of CBL0137 treatment to delineate the effect of CBL0137 treatment on global transcriptome of 4T1.2 tumours.. CBL0137 and NKG2A blockade: a novel immuno-oncology combination therapy for Myc-overexpressing triple-negative breast cancers

The MYC proto-oncogene is upregulated in >60% of triple-negative breast cancers (TNBCs), it can directly promote tumor cell proliferation and its overexpression negatively regulates anti-tumor immune responses. For all these reasons, MYC has long been considered as a compelling therapeutic target. However, pharmacological inhibition of MYC function has proven difficult due to a lack of a drug-binding pocket. Here, we demonstrate that the potent abrogation of MYC gene transcription by the FACT complex inhibitor CBL0137 selectively induces immunogenic cell death and reduces proliferation in MYC-high but not in MYC-low BC cells in vitro. CBL0137 also significantly reduced the in vivo growth of primary tumors and brain metastasis in a human MYC-high BC model (MDA-MB-231). Moreover, CBL0137 inhibited the tumor growth of mouse 4T1.2 BC in immunocompetent mice by inhibiting the MYC pathway and inducing Type I interferon responses. Immune profiling of CBL0137-treated mice revealed significantly enhanced tumor-specific immune responses and increased proportions of tumor infiltrating effector CD8+ T cells, CD4+ T cells, and NK cells. CBL0137-induced immune activation also resulted in increased exhaustion of immune effector cells. In particular, NKG2A up-regulation on activated effector cells and of its ligand Qa-1b on tumors in vivo was identified as a possible immune evasive mechanism. Indeed, NKG2A blockade synergized with CBL0137 significantly inhibiting the in vivo growth of 4T1.2 tumors. Collectively, our findings provide the rationale supporting the exploitation of CBL0137-induced anti-tumor immunity in combination with NKG2A blockade to improve the treatment of TNBC expressing high levels of MYC.