MYC amplification sensitizes TNBC to CHK1 inhibitors

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, for which effective therapy is urgently needed. We demonstrated that MYC overexpression was associated with TNBC subtype and promoted the cell proliferation, invasion and migration in TNBC cells. Moreover, MYC overexpression induced replication stress and DNA damage in TNBC cells. Our subsequent results revealed that the novel second-generation CHK1 inhibitor, prexasertib, exhibited a more pronounced inhibitory effect in MYC-overexpressed TNBC cells compared to other DNA damage repair inhibitors, including ATR, WEE1, and PARP inhibitors. Prexasertib induced synergistic lethality with MYC-overexpressed TNBC cells by generating excessive DNA damage. Intriguingly, RNA-seq analysis identified an increase in MYC levels and activation of MYC-related pathways following prexasertib treatment, while western blot results showed that prexasertib led to MYC protein degradation independent of proteasome pathway. In addition, MYC overexpression was associated with an immunosuppressive microenvironment and high PD-L1 expression. Prexasertib activated cGAS-STING pathway by inducing DNA damage. Therefore, combination of prexasertib and immune checkpoint inhibitors will be a potential therapeutic strategy for MYC-overexpressed TNBC. In conclusion, our findings demonstrated that MYC overexpression characterizes an aggressive TNBC subtype, enabling synergistic lethality with CHK1 inhibitors. CHK1 inhibitors will be a potential therapeutic strategy in TNBC patients with MYC overexpression.