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

• Published in: Cell reports (Cambridge) Vol. 34; no. 9; p. 108808
• Main Authors: Branigan, Timothy B., Kozono, David, Schade, Amy E., Deraska, Peter, Rivas, Hembly G., Sambel, Larissa, Reavis, Hunter D., Shapiro, Geoffrey I., D’Andrea, Alan D., DeCaprio, James A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.03.2021
• Subjects: A549 Cells; Antineoplastic Agents - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; CDK1; cell cycle checkpoint; Cell Cycle Checkpoints - drug effects; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Checkpoint Kinase 1 - antagonists & inhibitors; Checkpoint Kinase 1 - genetics; Checkpoint Kinase 1 - metabolism; CHK1; Forkhead Box Protein M1 - genetics; Forkhead Box Protein M1 - metabolism; FOXM1; Gene Expression Regulation, Neoplastic; Humans; LIN54; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mitosis - drug effects; Multiprotein Complexes; MuvB; MYBL2; non-small-cell lung cancer; prexasertib; Protein Kinase Inhibitors - pharmacology; Pyrazines - pharmacology; Pyrazoles - pharmacology; Signal Transduction; Trans-Activators - genetics; Trans-Activators - metabolism; MuvB; LIN54; CHK1; cell cycle checkpoint; prexasertib; CDK1; MYBL2; FOXM1; non-small-cell lung cancer
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.108808

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. [Display omitted] •The MMB-FOXM1 complex components are required for CHK1i sensitivity•CHK1i prematurely activates the G2/M transcriptional program by MMB-FOXM1•Mitotic pH3 induced by CHK1i during S phase requires the MMB-FOXM1 complex•Premature mitosis is required for replication catastrophe after CHK1 inhibition 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.