MMB-FOXM1-driven premature mitosis is required for CHK1 inhibitor sensitivity

SUMMARY

To identify genes whose loss confers resistance to CHK1 inhibitors, we perform genome-wide CRISPR-Cas9 screens in non-small-cell lung cancer (NSCLC) cell lines treated with the CHK1 inhibitor prexasertib (CHK1i). Five of the top six hits of the screens, MYBL2 (B-MYB), LIN54, FOXM1, cyclin A2 (CCNA2), and CDC25B, are cell-cycle-regulated genes that contribute to entry into mitosis. Knockout of MMB-FOXM1 complex components LIN54 and FOXM1 reduce CHK1i-induced DNA replication stress markers and premature mitosis during Late S phase. Activation of a feedback loop between the MMB-FOXM1 complex and CDK1 is required for CHK1i-induced premature mitosis in Late S phase and subsequent replication catastrophe, indicating that dysregulation of the S to M transition is necessary for CHK1 inhibitor sensitivity. These findings provide mechanistic insights into small molecule inhibitors currently studied in clinical trials and provide rationale for combination therapies.

Graphical Abstract

In brief

Branigan et al., by using genome-wide CRISPR screens, identify the MMB-FOXM1 complex as being required for CHK1 inhibitor (CHK1i) sensitivity. Their study shows that CHK1i-induced premature activation of the G2/M transcriptional program by this complex triggers a breakdown in the separation of DNA synthesis and mitosis, leading to replication catastrophe.