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

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)...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2021-03, Vol.34 (9), p.108808-108808, Article 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: Article
Language:English
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
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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. [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.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2021.108808